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  • 1.
    Ahl, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Liu, Haoyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Schreiber, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Roos, S.
    Swedish Univ Agr Sci, Uppsala BioCtr, Dept Microbiol, Uppsala, Sweden..
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lactobacillus reuteri increases mucus thickness and ameliorates dextran sulphate sodium-induced colitis in mice2016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 217, no 4, 300-310 p.Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this study was to investigate whether two Lactobacillus reuteri strains (rat-derived R2LC and human-derived ATCC PTA 4659 (4659)) could protect mice against colitis, as well as delineate the mechanisms behind this protection.

    Methods: Mice were given L.reuteri R2LC or 4659 by gavage once daily for 14days, and colitis was induced by addition of 3% DSS (dextran sulphate sodium) to drinking water for the last 7days of this period. The severity of disease was assessed through clinical observations, histological evaluation and ELISA measurements of myeloperoxidase (MPO) and pro-inflammatory cytokines from colonic samples. Mucus thickness was measured invivo with micropipettes, and tight junction protein expression was assessed using immunohistochemistry.

    Results: Colitis severity was significantly reduced by L.reuteri R2LC or 4659 when evaluated both clinically and histologically. The inflammation markers MPO, IL-1, IL-6 and mKC (mouse keratinocyte chemoattractant) were increased by DSS and significantly reduced by the L.reuteri strains. The firmly adherent mucus thickness was reduced by DSS, but significantly increased by L.reuteri in both control and DSS-treated mice. Expression of the tight junction proteins occludin and ZO-1 was significantly increased in the bottom of the colonic crypts by L.reuteri R2LC.

    Conclusion: These results demonstrate that each of the two different L. reuteri strains, one human-derived and one-rat-derived, protects against colitis in mice. Mechanisms behind this protection could at least partly be explained by the increased mucus thickness as well as a tightened epithelium in the stem cell area of the crypts.

  • 2.
    Anderberg, S. B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Luther, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Physiological aspects of Toll-like receptor 4 activation in sepsis-induced acute kidney injury2017In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 219, no 3, 575-590 p.Article, review/survey (Refereed)
    Abstract [en]

    Sepsis-induced acute kidney injury (SI-AKI) is common and associated with high mortality. Survivors are at increased risk of chronic kidney disease. The precise mechanism underlying SI-AKI is unknown, and no curative treatment exists. Toll-like receptor 4 (TLR4) activates the innate immune system in response to exogenous microbial products. The result is an inflammatory reaction aimed at clearing a potential infection. However, the consequence may also be organ dysfunction as the immune response can cause collateral damage to host tissue. The purpose of this review is to describe the basis for how ligand binding to TLR4 has the potential to cause renal dysfunction and the mechanisms by which this may take place in gram-negative sepsis. In addition, we highlight areas for future research that can further our knowledge of the pathogenesis of SI-AKI in relation to TLR4 activation. TLR4 is expressed in the kidney. Activation of TLR4 causes cytokine and chemokine release as well as renal leucocyte infiltration. It also results in endothelial and tubular dysfunction in addition to altered renal metabolism and circulation. From a physiological standpoint, inhibiting TLR4 in large animal experimental SI-AKI significantly improves renal function. Thus, current evidence indicates that TLR4 has the ability to mediate SI-AKI by a number of mechanisms. The strong experimental evidence supporting a role of TLR4 in the pathogenesis of SI-AKI in combination with the availability of pharmacological tools to target TLR4 warrants future human studies.

  • 3. Asgeirsson, D.
    et al.
    Venturoli, D.
    Fries, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rippe, B.
    Rippe, C.
    Glomerular sieving of three neutral polysaccharides, polyethylene oxide and bikunin in rat. Effects of molecular size and conformation2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 191, no 3, 237-246 p.Article in journal (Refereed)
    Abstract [en]

    Aim: Polysaccharides and many other non-protein polymers generally have a more open, flexible and asymmetrical structure compared with globular proteins. For a given molecular weight (MW), the Stokes–Einstein radius (ae) of the following polymers increases in the order: Ficoll < dextran ≤ pullulan < polyethylene oxide (PEO). We have tested the hypothesis that such an increase in 'molecular extension' will increase the molecule's glomerular permeability. Thus, we investigated the glomerular sieving coefficients (θ) of the mentioned polymers and of the negatively charged and extended protein bikunin.

    Methods: In anaesthetized Wistar rats, glomerular sieving curves were generated for each FITC-labelled polymer from their respective concentration in urine and plasma, determined by size exclusion chromatography. The θ for bikunin was measured using a tissue uptake technique.

    Results: For a molecule of ae = 55 Å (cf. IgG), θ increased in the order: Ficoll (0.00035 ± 0.000013) < dextran (0.022 ± 0.0029) < pullulan (0.033 ± 0.0024) < PEO (0.12 ± 0.0055). For ae = 36 Å (cf. albumin) the order was: Ficoll (0.076 ± 0.0061) < dextran (0.45 ± 0.037) = pullulan (0.45 ± 0.021) < PEO (0.65 ± 0.0076). θ for bikunin (0.089 ± 0.0045) was 150 times higher than that of albumin, having an equivalent ae and net negative charge.

    Conclusion: From these results it is concluded that for flexible and asymmetric macromolecules, their degree of glomerular hyperpermeability is proportional to their degree of 'molecular extension'. Thus, compared with globular proteins, the polysaccharides investigated, including Ficoll, were found to be hyperpermeable across the glomerular filter in vivo.

  • 4.
    Babateen, Omar M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nilsson, Karin Forsberg
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    GABA-A receptor currents in a cell line (U3047MG) derived from a human glioblastoma tumor are enhanced by etomidate, propofol and diazepam2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, 100-100 p., P74Article in journal (Other academic)
  • 5.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The left-right neurohormonal regulation in the brain: Lateralized endogenous opioid system2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, 12-12 p.Article in journal (Other academic)
  • 6.
    Barg, Sebastian
    et al.
    Department of Cell Biology, Division of Medicine, Imperial College, London, UK.
    Machado, Jose David
    Compensatory endocytosis in chromaffin cells2008In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 192, no 2, 195-201 p.Article, review/survey (Refereed)
    Abstract [en]

    Exocytosis occurs via fusion of secretory granules with the cell membrane, whereupon the granule content is at least partially released and the granule membrane is temporarily added to the plasma membrane. Exocytosis is balanced by compensatory endocytosis to achieve net equilibrium of the cell surface area and to recycle and redistribute components of the exocytosis machinery. The underlying molecular mechanisms remain a matter of debate. In this review, we summarize and discuss recent progress in the understanding of compensatory endocytosis, with the focus on chromaffin cells as a useful model for studying mechanisms of regulated secretion.

  • 7. Barragan, A.
    et al.
    Weidner, J. M.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korpi, E. R.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABAergic signalling in the immune system2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 4, 819-827 p.Article, review/survey (Refereed)
    Abstract [en]

    The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates. Signalling of the transmitter c-aminobutyric acid (GABA) via GABA type A receptor channels or G-protein-coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/GABA-A receptor-mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma-infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain-derived neurotrophic factor. The neurotransmitter-driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research.

  • 8.
    Bengtsson, Magnus W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Jedstedt, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Duodenal bicarbonate secretion in rats: Stimulation by intra-arterial and luminal guanylin and uroguanylin2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 191, no 4, 309-317 p.Article in journal (Refereed)
    Abstract [en]

    Aim: Uroguanylin and guanylin are endogenous ligands for guanylate cyclase C, an upstream regulator of the cystic fibrosis transmembrane resistance (CFTR) anion channel, and both peptides increase intestinal anion export in vitro. We have compared the effects of close intra-arterial and luminal administration of uroguanylin and guanylin on duodenal bicarbonate secretion in vivo and studied the interactions with melatonin and cholinergic stimulation.

    Methods: Lewis × Dark Agouti rats were anaesthetized and a segment of the proximal duodenum with intact blood supply was cannulated in situ. Mucosal bicarbonate secretion (pH stat) was continuously recorded and peptides were infused intra-arterially or added to the luminal perfusate.

    Results: Intra-arterial (50–1000 pmol kg−1 h−1) as well as luminal administration (50–500 nmol L−1) of guanylin or uroguanylin caused dose-dependent increases in the duodenal secretion. Luminal administration induced more rapidly appearing rises in secretion and the two peptides induced secretory responses of similar shape and magnitude. The melatonin MT2-selective antagonist luzindole (600 nmol kg−1) significantly depressed the response to intra-arterial guanylins but did not affect secretion induced by luminal guanylins. Similarly, the muscarinic antagonist atropine (0.75 μmol kg−1 followed by 0.15 μmol kg−1 h−1) abolished the response to intra-arterial uroguanylin but caused only slight suppression of the response to luminal uroguanylin.

    Conclusions: Intra-arterial as well as luminal uroguanylin and guanylin are potent stimuli of duodenal mucosal bicarbonate secretion in vivo. The response to luminal guanylins reflects an action at apical receptors. Stimulation by parenteral guanylins, in contrast, is under cholinergic influence and interacts with melatonin produced by mucosal enteroendocrine cells.

  • 9.
    Bhandage, Amol
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Ólafsson, Einar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    The mRNA expression of GABA-A, GABA-B receptor subunits and chloride transporters in peripheral blood mononuclear cells is influenced by gender, pregnancy and depression2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, 91-91 p.Article in journal (Other academic)
  • 10.
    Bhandage, Amol K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Olafsson, Einar B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 3, 575-585 p.Article in journal (Refereed)
    Abstract [en]

    AIM: The concept of nerve-driven immunity recognizes a link between the nervous and the immune system. γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain and receptors activated by GABA can be expressed by immune cells. Here we examined if the expression of GABA receptors and chloride transporters in human peripheral mononuclear cells (PBMCs) were influenced by gender, pregnancy or mental health.

    METHODS: We used RT-qPCR to determine the mRNA expression level in men (n=16), non-pregnant women (n=19), healthy pregnant women (n=27) and depressed pregnant women (n=15).

    RESULTS: The ρ2 subunit had the most prominent expression level of the GABA-A receptor subunits in all samples. The δ and ρ2 subunits were up-regulated by pregnancy whereas the ε subunit was more frequently expressed in healthy pregnant women than non-pregnant women who, in-turn, commonly expressed the α6 and the γ2 subunits. The β1 and ε subunits expression was altered by depression in pregnant women. The GABA-B1 receptor was up-regulated by depression in pregnant women while the transporters NKCC1 and KCC4 were down-regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs.

    CONCLUSION: The results demonstrate the impact gender, pregnancy and mental health have on expression of GABA receptors plus chloride transporters expressed in human PBMCs.

  • 11.
    Bhandage, Amol K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Olafsson, Einar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundström, Iinger Poromaa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA-A receptor subunit expression in human peripheral blood mononuclear cells2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, 86-86 p., P45Article in journal (Other academic)
  • 12.
    Broche, Ludovic
    et al.
    Grenoble, France..
    Gaetano, Perchiazzi
    Univ Bari, Bari, Italy..
    Liisa, Porra
    Univ Helsinki, Helsinki, Finland..
    Angela, Tannoia
    Univ Bari, Bari, Italy..
    Mariangela, Pellegrini
    Univ Bari, Bari, Italy..
    Savino, Derosa
    Univ Bari, Bari, Italy..
    Alessandra, Sindaco
    Univ Bari, Bari, Italy..
    Borges, João Batista
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Loic, Degrugilliers
    Univ Picardie Jules Verne, Amiens, France..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Anthony, Wexler
    Univ Calif Davis, Davis, CA 95616 USA..
    Alberto, Bravin
    ESRF, Grenoble, France..
    Sylvia, Verbanck
    Univ Hosp UZ Brussel, Brussels, Belgium..
    Bradford, J. Smith
    Univ Vermont, Burlington, VT USA..
    Jason, H. T. Bates
    Univ Vermont, Burlington, VT USA..
    Sam, Bayat
    Univ Picardie Jules Verne, Amiens, France..
    Dynamic mechanical interactions between neighboring airspaces determine cyclic opening and closure in injured lung2016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 217, 141-141 p.Article in journal (Other academic)
  • 13.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Brown, Russell D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yang, T.
    Hezel, M.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Scheffer, P. G.
    Teerlink, T.
    Lundberg, J. O.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    L-arginine or tempol supplementation improves renal and cardiovascular function in rats with reduced renal mass and chronic high salt intake2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 207, no 4, 732-741 p.Article in journal (Refereed)
    Abstract [en]

    Aim Early life reduction in nephron number and chronic high salt intake cause development of renal and cardiovascular disease, which has been associated with oxidative stress and nitric oxide (NO) deficiency. We investigated the hypothesis that interventions stimulating NO signalling or reducing oxidative stress may restore renal autoregulation, attenuate hypertension and reduce renal and cardiovascular injuries following reduction in renal mass and chronic high salt intake. Methods Male SpragueDawley rats were uninephrectomized (UNX) or sham-operated at 3weeks of age and given either a normal-salt (NS) or high-salt (HS) diet. Effects on renal and cardiovascular functions were assessed in rats supplemented with substrate for NO synthase (L-Arg) or a superoxide dismutase mimetic (Tempol). Results Rats with UNX+HS developed hypertension and displayed increased renal NADPH oxidase activity, elevated levels of oxidative stress markers in plasma and urine, and reduced cGMP in plasma. Histological analysis showed signs of cardiac and renal inflammation and fibrosis. These changes were linked with abnormal renal autoregulation, measured as a stronger tubuloglomerular feedback (TGF) response. Simultaneous treatment with L-Arg or Tempol restored cGMP levels in plasma and increased markers of NO signalling in the kidney. This was associated with normalized TGF responses, attenuated hypertension and reduced signs of histopathological changes in the kidney and in the heart. Conclusion Reduction in nephron number during early life followed by chronic HS intake is associated with oxidative stress, impaired renal autoregulation and development of hypertension. Treatment strategies that increase NO bioavailability, or reduce levels of reactive oxygen species, were proven beneficial in this model of renal and cardiovascular disease.

  • 14.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Skott, Ole
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wåhlin, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating ability in mice2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, no 3, 293-301 p.Article in journal (Refereed)
    Abstract [en]

    Aim: Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt-sensitive hypertension in rats. The mechanisms are still unclear, but appear to be intrarenal and primarily located to the diseased kidney. In the present study, we have developed a model for PUUO to study if hydronephrotic mice develop salt-sensitive hypertension.

    Methods: PUUO was created in 3-week-old mice (C57bl/6J). Blood pressure and heart rate were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated.

    Results: All hydronephrotic animals developed salt-sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 ± 1 mmHg on normal salt diet to 120 ± 2 mmHg on high salt diet, compared with 103 ± 1 to 104 ± 1 in controls. Hydronephrotic animals showed increased diuresis and reduced ability to regulate electrolyte concentration. No differences in plasma renin concentration were found between the groups. The parenchymal weight and glomerular area of contralateral kidneys were significantly increased in the hydronephrotic animals. Histopathology of the hydronephrotic kidneys displayed areas with fibrosis, inflammation and glomerular changes.

    Conclusion: This study provides a model for PUUO in mice and demonstrates the presence of salt-sensitive hypertension and an impaired renal concentrating ability in mice which has not been described before.

  • 15.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Wåhlin, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Skott, Ole
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Relief of chronic partial ureteral obstruction attenuates salt-sensitive hypertension in rats2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, no 1, 67-75 p.Article in journal (Refereed)
    Abstract [en]

    Aim: The incidence of hydronephrosis due to ureteropelvic junction obstruction is approx. 0.5%. During the last decade, the management of non-symptomatic hydronephrosis has become much more conservative, but the long-term physiological consequences of this policy are not clear. Previously, we have shown that animals with chronic partial unilateral ureteral obstruction develop salt-sensitive hypertension. In this study, the effects of ipsilateral and contralateral nephrectomy and ureterovesicostomy on blood pressure were studied in hydronephrotic animals.

    Methods: Partial unilateral ureteral obstruction was created in 3-week-old male Sprague–Dawley rats and blood pressure was measured telemetrically 4–6 weeks later during a normal and high salt diet before and after uninephrectomy or ureterovesicostomy. Plasma samples for renin assay were collected during both diets before and after ipsilateral nephrectomy.

    Results: All hydronephrotic animals developed salt-sensitive hypertension, of different degrees. Before nephrectomy the plasma renin concentration was significantly higher in the hydronephrotic animals than in controls (160 ± 15 μGU mL−1 vs. 96 ± 12 μGU mL−1, respectively), but after the ipsilateral nephrectomy no differences were found between the groups. In the hydronephrotic animals both ipsilateral nephrectomy and ureterovesicostomy reduced the blood pressure and salt-sensitivity but the former still differed significantly from the controls. In contralaterally, nephrectomized hydronephrotic animals the salt-sensitive hypertension became more pronounced.

    Conclusion: Hydronephrosis in rats causes salt-sensitive hypertension that can be markedly reduced by removing the hydronephrotic kidney or relieving the obstruction by ureterovesicostomy. The mechanisms appear to be intrarenal and primarily located in the diseased kidney, but a secondary mechanism is also present.

  • 16.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    On the physiology of vascular permeability2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, 19-19 p.Article in journal (Other academic)
  • 17.
    Comasco, E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Rangmar, J
    Eriksson, U J
    Oreland, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neurological and neuropsychological effects of low and moderate prenatal alcohol exposure.2017In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716Article in journal (Refereed)
    Abstract [en]

    Several explanations for the diverse results in research on foetal alcohol spectrum disorders or alcohol-related neurodevelopmental disorder might be at hand: timing, amount and patterns of alcohol exposure, as well as complex epigenetic responses. The genetic background of the offspring and its interaction with other prenatal and post-natal environmental cues are likely also of importance. In the present report, key findings about the possible effects of low and moderate doses of maternal alcohol intake on the neuropsychological development of the offspring are reviewed and plausible mechanisms discussed. Special focus is put on the serotonergic system within developmental and gene-environment frameworks. The review also suggests guidelines for future studies and also summarizes some of to-be-answered questions of relevance to clinical practice. Contradictory findings and paucity of studies on the effects of exposure to low alcohol levels during foetal life for the offspring's neuropsychological development call for large prospective studies, as well as for studies including neuroimaging and multi-omics analyses to dissect the neurobiological underpinnings of alcohol exposure-related phenotypes and to identify biomarkers. Finally, it remains to be investigated whether any safe threshold of alcohol drinking during pregnancy can be identified.

  • 18.
    Cristea, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Korhonen, Marko
    Häkkinen, Keijo
    Mero, Antti
    Alén, Markku
    Sipilä, Sarianna
    Viitasalo, Jukka
    Koljonen, Martti
    Suominen, Harri
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Effects of combined strength and sprint training on regulation of muscle contraction at the whole-muscle and single fibre levels in elite master sprinters2008In: Acta Physiologica, ISSN 1748-1708, Vol. 193, no 3, 275-289 p.Article in journal (Refereed)
    Abstract [en]

    AIM: This study aims at examining the effects of progressive strength and sprint training on regulation of muscle contraction at the whole-muscle and single-fibre levels in older sprint-trained athletes. METHODS: Eleven men (52-78 years) were randomized to a training (EX, n = 7) or control (CTRL, n = 4) group. EX participated in a 20-week programme that combined sprint training with heavy and explosive strength exercises, while CTRL maintained their usual run-based training schedules. RESULTS: EX improved maximal isometric and dynamic leg strength, explosive jump performance and force production in running. Specific tension and maximum shortening velocity of single fibres from the vastus lateralis were not altered in EX or CTRL. Fibre type and myosin heavy chain isoform distributions remained unchanged in the two groups. There was a general increase in fibre areas in EX, but this was significant only in IIa fibres. The 10% increase in squat jump in EX was accompanied by a 9% increase in the integrated EMG (iEMG) of the leg extensors but the 21-40% increases in isometric and dynamic strength were not paralleled by changes in iEMG. CONCLUSION: Adding strength training stimulus to the training programme improved maximal, explosive and sport-specific force production in elite master sprinters. These improvements were primarily related to hypertrophic muscular adaptations.

  • 19. Danielsson, T
    et al.
    Fredriksson, L
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Henriksnäs, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Resistin increases islet blood flow and decreases subcutaneous adipose tissue blood flow in anaesthetized rats2009In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 195, no 2, 283-288 p.Article in journal (Refereed)
    Abstract [en]

    AIM: Resistin is an adipokine which has been suggested to participate in the induction of insulin resistance associated with type 2 diabetes. The aim of the present study was to investigate whether acute administration of resistin influences tissue blood perfusion in rats. METHODS: Resistin was administered as an intravenous infusion of 7.5 microg h(-1) (1.5 mL h(-1)) for 30 min to rats anaesthetized with thiobutabarbital. A microsphere technique was used to estimate the blood flow to six different depots of white adipose tissue (WAT), brown adipose tissue (BAT), as well as to the pancreas, islets, duodenum, colon, kidneys, adrenal glands and liver. RESULTS: Resistin administration led to an increased blood flow to the pancreas and islets and a decrease in subcutaneous WAT and BAT. Intra-abdominal white adipose tissue blood flow and that to other organs were not affected. CONCLUSION: Acute administration of resistin markedly affects the blood perfusion of both the pancreas and subcutaneous white adipose tissue depots. At present it is unknown whether resistin exerts a direct effect on the vasculature, or works through local or systemic activation of endothelial cells and/or macrophages. The extent to which this might contribute to the insulin resistance caused by resistin is yet unknown.

  • 20.
    Ekenros, L.
    et al.
    Karolinska Inst, Div Physiotherapy, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden..
    Papoutsi, Zoi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Novum, Dept Biosci & Nutr, Huddinge, Sweden..
    Friden, C.
    Karolinska Inst, Div Physiotherapy, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.;St Erik Primary Hlth Care Ctr, Acad Primary Hlth Care Ctr, Stockholm, Sweden..
    Wright, K. Dahlman
    Karolinska Inst, Novum, Dept Biosci & Nutr, Huddinge, Sweden..
    Hirschberg, A. Linden
    Karolinska Inst, Div Obstet & Gynecol, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Expression of sex steroid hormone receptors in human skeletal muscle during the menstrual cycle2017In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 219, no 2, 486-493 p.Article in journal (Refereed)
    Abstract [en]

    Aim: Variations in sex hormone levels during the menstrual cycle may affect neuromuscular performance and the risk of sustaining musculoskeletal injury in women. The aim of this study was to investigate mRNA and protein levels for sex steroid hormone receptors in skeletal muscle in three distinct phases of the menstrual cycle. Methods: Fifteen, healthy women with regular menstrual cycles participated in the study. Muscle biopsies from the vastus lateralis were obtained in three hormonally verified phases of the menstrual cycle for each individual, that is the follicular phase, the ovulatory phase and the luteal phase. mRNA and protein levels of oestrogen (ER and ER), progesterone (PR) and androgen (AR) receptors were analysed. Results: There was an overall significant variation in mRNA and protein levels of ER and PR across the menstrual cycle. mRNA and protein levels of ER were highest in the follicular phase when oestradiol levels were low, whereas protein levels of PR were highest in the luteal phase when progesterone levels were high. mRNA levels of PR were highest in the ovulatory phase. No significant variation in AR levels was detected across the menstrual cycle. ER levels were very low in all three phases of the menstrual cycle. Conclusion: Significant variations in mRNA and protein levels of ER and PR were detected in skeletal muscle during three confirmed phases of the menstrual cycle. These results may have an impact on effects of muscular training and sports injuries in women.

  • 21.
    Ekholm, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Johansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Kukkonen, Jyrki P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Rapid and easy semi-quantitative evaluation method for diacylglycerol and inositol-1,4,5-trisphosphate generation in orexin receptor signalling2010In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 198, no 3, 387-392 p.Article in journal (Refereed)
    Abstract [en]

    Aim: Fluorescent protein-based indicators have enabled measurement of intracellular signals previously nearly inaccessible for studies. However, indicators showing intracellular translocation upon response suffer from serious limitations, especially the very time-consuming data collection. We therefore set out in this study to evaluate whether fixing and counting cells showing translocation could mend this issue.

    Methods: Altogether three different genetically encoded indicators for diacylglycerol and inositol-1,4,5-trisphosphate were transiently expressed in Chinese hamster ovary cells stably expressing human OX1 orexin receptors. Upon stimulation with orexin-A, the cells were fixed with six different protocols.

    Results: Different protocols showed clear differences in their ability to preserve the indicator’s localization (i.e. translocation after stimulus) and its fluorescence, and the best results for each indicator were obtained with a different protocol. The concentration

    Conclusion: The counting method, as used here, works at single time point and looses the single-cell-quantitative aspect. However, it also has some useful properties. First, it easily allows processing of a 100- to 1000-fold higher cell numbers than real-time imaging producing statistically consistent population-quantitative data much faster. Secondly, it does not require expensive real-time imaging equipment. Fluorescence in fixed cells can also be quantitated, though this analysis would be more time-consuming than cell counting. Thirdly, in addition to the quantitative data collection, the method could be applied for identifying responsive cells. This might be very useful in identification of e.g. orexin-responding neurones in a large population of non-responsive cells in primary cultures.

  • 22.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bengtsson, Magnus Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Mäkelä, Kari Antero
    Inst. of Biomedicine, Div. of Physiology, Oulu Univ., Oulu, Finland.
    Herzig, Karl-Heinz
    Inst. of Biomedicine, Div. of Physiology, Oulu Univ., Oulu, Finland.
    Effects of short-term food deprivation on orexin-A-induced intestinal bicarbonate secretion in comparison with related secretagogues2010In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 198, no 3, 373-380 p.Article, review/survey (Refereed)
    Abstract [en]

    Studies of gastrointestinal physiology in humans and intact animals are usually conducted after overnight fast. We have compared effects of orexin-A, vasoactive intestinal polypeptide (VIP), melatonin, serotonin, uroguanylin, ghrelin and prostaglandin E2 (PGE2) on duodenal bicarbonate secretion in fed and overnight fasted animals. This review is a summary of our findings. Secretagogues  were administered by intra-arterial infusion or luminally (PGE2) Enterocyte intracellular calcium ([Ca2+]i) signaling was studied by fluorescence imaging. Total RNA was extracted, reverse transcripted to cDNA and expression of orexin receptors measured by quantitative real-time PCR.

    Orexin-A stimulates the duodenal secretion in continuously fed animals but not in food deprived animals. Similarly, short fasting causes a 100-fold decrease  of the amount of the muscarinic agonist bethanechol required for stimulation of secretion. In contrast, fasting does not affect secretory responses to intra-arterial VIP, melatonin, serotonin, uroguanylin and ghrelin, or that to luminal PGE2. Orexin-A induces [Ca2+]i signaling in enterocytes from fed rats but no significant [Ca2+]i responses occurs in enterocytes from fasted animals. In addition, overnight fasting decreases the expression of mucosal and enterocyte orexin receptors.

    Short food deprivation thus decreases duodenal expression of orexin receptors and abolishes the secretory response to orexin-A as well as orexin-A induced [Ca2+]i signaling. Fasting, furthermore, decreases mucosal sensitivity to bethanechol. The absence of declines in secretory responses to other secretagogues tested is strong evidence that short fasting does affect not the secretory capacity of the duodenal mucosa in general. Studies of intestinal secretion require particular evaluation with respect to feeding status.

  • 23.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Mäkelä, Kari
    University of Oulu, Oulu, Finland.
    Purhonen, Anna-Kaisa
    University of Oulu, Oulu, Finland.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jedstedt, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Walkowiak, Jan
    University of Medical Sciences, Poznan, Poland.
    Herzig, Karl-Heinz
    University of Oulu, Oulu, Finland.
    Apelin stimulation of duodenal bicarbonate secretion: feeding-dependent and mediated via apelin-induced release of enteric cholecystokinin2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 201, no 1, 141-150 p.Article in journal (Refereed)
    Abstract [en]

    Aim: Apelin peptides is the endogenous ligand of the G protein-coupled receptor APJ. Proposed actions include involvement in control of cardiovascular functions, appetite and body metabolism. We have investigated effects of apelin peptides on duodenal bicarbonate secretion in vivo and the release of cholecystokinin (CCK) from acutely isolated mucosal cells and the neuroendocrine cell line STC-1. Methods: Lewis x Dark Agouti rats had free access to water and, unless fasted overnight, free access  to food. A segment of proximal duodenum was cannulated in situ in anesthetized animals. Mucosal bicarbonate secretion was titrated (pH stat) and apelin was administered to the duodenum by close intra-arterial infusion. Total RNA was extracted from mucosal specimens, reverse transcripted to cDNA and expression of the APJ receptor measured by quantitative real-time PCR. Apelin-induced release of CCK was measured using (i) cells prepared from proximal small intestine, and (ii) STC-1 cells. Results: Even the lowest dose of apelin-13 (6 pmol kg-1 h-1) caused a significant rise in bicarbonate secretion. Stimulation occurred only in continuously fed animals and even a 100-fold greater dose (600 pmol kg-1 h-1) of apelin was without effect in overnight food deprived animals. Fasting also induced a 8-fold decrease  in the expression of APJ receptor mRNA. Apelin induced significant release of CCK from both mucosal and STC-1 cells, and the CCKA receptor antagonist devazepide abolished bicarbonate secretory responses to apelin. Conclusions: Apelin-induced stimulation of duodenal electrolyte secretion is feeding dependent and mediated by local mucosal release of CCK

     

  • 24. Franzen, S.
    et al.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Endothelin receptor A blockade normalizes kidney tissue hypoxia in type-1 diabetic rats2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, 79-79 p., P31Article in journal (Other academic)
  • 25.
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Toll-like receptor 4 in sepsis-induced renal failure2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, 39-39 p., 7:3Article in journal (Other academic)
  • 26.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Peleli, M.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlstrom, M.
    Role of adenosine A(1) receptor dependent and independent pathways in modulating renal vascular responses to angiotensin II2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, 81-81 p., P35Article in journal (Other academic)
  • 27.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Peleli, Maria
    Karolinska Institutet.
    Zollbrecht, Christa
    Karolinska Institutet.
    Patzak, Andreas
    Charité-Universitätsmedizin Berlin, Germany.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mattias, Carlström
    Karolinska Institutet.
    Adenosine A1 receptor-dependent and independent pathways in modulating renal vascular responses to angiotensin II2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 1, 268-276 p.Article in journal (Refereed)
    Abstract [en]

    AIM: Renal afferent arterioles are the effector site for autoregulation of glomerular perfusion and filtration. There is synergistic interaction between angiotensin II (ANG II) and adenosine (Ado) in regulating arteriolar contraction, however, the mechanisms are not clear. In this context, this study investigated the contribution of A1 receptor dependent and independent signaling mechanisms.

    METHODS: Isolated perfused afferent arterioles from transgenic mice (A1+/+ and A1-/-) were used for vascular reactivity studies. Cultured vascular smooth muscle cells (VSMC) were used for phosphorylation studies of signaling proteins that induce arteriolar contraction.

    RESULTS: Maximal arteriolar contraction to ANG II was attenuated in A1-/- (22%) compared with A1+/+ (40%). Simultaneous incubation with low dose Ado (10-8 mol/L) enhanced ANG II-induced contraction in A1+/+ (58%), but also in A1-/- (42%). An Ado transporter inhibitor (NBTI) abolished this synergistic effect in A1-/-, but not in wild-type mice. Incubation with Ado+ANG II increased p38 phosphorylation in aortic VSMC from both genotypes, but treatment with NBTI only blocked phosphorylation in A1-/-. Combination of ANG II+Ado also increased MLC phosphorylation in A1+/+ but not significantly in A1-/-, and NBTI had no effects. In agreement, Ado+ANG II-induced phosphorylation of p38 and MLC in rat preglomerular VSMC was not affected by NBTI. However, during pharmacological inhibition of the A1 receptor simultaneous treatment with NBTI reduced phosphorylation of both p38 and MLC to control levels.

    CONCLUSION: Interaction between ANG II and Ado in VSMC normally involves A1 receptor signaling, but this can be compensated by receptor independent actions that phosphorylate p38 MAPK and MLC.

  • 28. Gillberg, L.
    et al.
    Berg, S.
    de Verdier, P. J.
    Lindbom, L.
    Werr, J.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Effective treatment of mouse experimental colitis by alpha 2 integrin antibody: comparison with alpha 4 antibody and conventional therapy2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 207, no 2, 326-336 p.Article in journal (Refereed)
    Abstract [en]

    Aim To compare the therapeutic effect of a2 and a4 integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate, 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model. Methods Colitis was induced in balb/c mice with 2.53.0% dextran sulphate sodium. Treatment was given daily for 7 days after the onset of colitis, by rectal installation. Clinical signs of disease were assessed daily using a disease activity index. After 19 days, all animals were killed and colon samples collected for histological grading and mRNA/protein analysis. All treatment groups were compared with an untreated control group and a treatment group receiving dextran sulphate sodium alone to monitor the potential degree of clinical remission. Results Treatment with anti-a2 antibodies and methotrexate reduced the body weight loss. At the end of treatment, anti-a2 antibodies reduced rectal bleeding, while methotrexate reduced the disease activity index score. Histological evaluation showed that anti-a2 antibodies, methotrexate, 5-aminosalicylic acid and azathioprine treatment reduced the acute inflammation; methotrexate was the only treatment with effect on the crypt score. Compared with the dextran sulphate sodium alone group, the methotrexate group showed down-regulation of IL-1 beta at the mRNA level, while the anti-a2 antibody group displayed decreased protein expression of iNOS and IL-1 beta. Conclusions Specific blocking of extravascular trafficking of leucocytes with a2-antibodies could be a new beneficial drug target in inflammatory bowel disease.

  • 29.
    Halim, M. Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Boghus, Sandy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellstrom, Per. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomized trial of N-G-monomethyl-L-arginine effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, 105-118 p.Article in journal (Refereed)
    Abstract [en]

    Aim: The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using N-G-monomethyl-L-arginine (L-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron. Methods: Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor L-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using L-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry. Results: L-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. L-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated by L-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells. Conclusion: Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 30.
    Halim, Md Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Boghus, Sandy
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Dominic-Luc, Webb
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    M. Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, 105-118 p.Article in journal (Refereed)
    Abstract [en]

    Aim

    The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.

    Methods

    Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.

    Results

    l-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.

    Conclusion

    Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 31.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    NADPH-oxidase-driven oxidative stress during experimental diabetes offsets NO-mediated regulation of renal medullary sodium transport. A potential treatment modality during type 1 diabetes?2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 209, no 2, 94-94 p.Article in journal (Other academic)
  • 32.
    Hansell, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    A role for the extracellular matrix component hyaluronan in kidney dysfunction during ACE-inhibitor fetopathy2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 4, 795-804 p.Article in journal (Refereed)
    Abstract [en]

    Despite data showing that inhibitors of the renin-angiotensin system increase the risks of fetal morbidity and dysfunctionality later in life, their use during pregnancy has increased. The fetopathy induced by angiotensin converting enzyme (ACE) inhibitors is characterized by anuria, hypotension and growth restriction, but can also be associated with pulmonary hypoplasia. In the kidney, this fetopathy includes atrophy of the medulla, reduced number of glomeruli, developmental lesions of tubules and vessels, tubulointerstitial inflammation and extracellular matrix accumulation. Although angiotensin II (Ang II) inhibition during nephrogenesis interferes with normal growth and development, this review will focus on effects of the heavily accumulated matrix component hyaluronan (HA). An important mechanism of HA accumulation during nephrogenesis is disruption of its normal reduction as a consequence of lack of Ang II activation of hyaluronidase. Hyaluronan has very large water-attracting properties and is pro-inflammatory when fragmented. The ensuing inflammation and interstitial oedema affect kidney function. Hyaluronan is colocalized with CD44 overexpression and infiltrating immune cells. These properties make HA a plausible contributor to the observed structural and functional kidney defects associated with the fetopathy. Available data support an involvement of HA in kidney dysfunction of the foetus and during adulthood due to the physico-chemical characteristics of HA. No clinical treatment for HA accumulation exists. Treatment with the HA-degrading enzyme hyaluronidase and an HA synthesis inhibitor has been tested successfully in experimental models in the kidney, heart and pancreas. Reduced HA accumulation to reduce interstitial oedema and inflammation may improve organ function, but this concept needs to be tested in a controlled study before causal relationships can be established.

  • 33.
    Hellman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Grapengiesser, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose-induced inhibition of insulin secretion2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 210, no 3, 479-488 p.Article, review/survey (Refereed)
    Abstract [en]

    Increase in glucose is known to elevate the concentration of cytoplasmic Ca2+ ([Ca2+](i)) in pancreatic -cells and stimulate insulin secretion. However, rise of glucose can also lower [Ca2+](i) and inhibit insulin release. In the present review, we examine the mechanisms for this inhibition and highlight its importance for the healthy -cell and the development of diabetes. It is possible to distinguish between 60 and 90s of prompt inhibition and the late inhibition seen after the first-phase peak of insulin release. The introductory inhibition is characteristic of the healthy -cell and mediated by sequestration of [Ca2+](i) in the endoplasmic reticulum. This inhibition is easily seen in studies of isolated islets but too brief to be detected in a conventional intravenous glucose tolerance test. Coupled to simultaneous rise of glucagon, the introductory suppression of insulin release is the starting point for the antiphase relation between the subsequent insulin and glucagon pulses. Another effect of the initial suppression is to increase the pool of readily releasable granules responsible for the first-phase release of insulin. The presence of late inhibition of insulin release is an indicator of -cell dysfunction. Patients with type 2 diabetes often respond to intravenous bolus injection of glucose with 5-10min of late suppression of circulating insulin.

  • 34.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    GLP-1 playing the role of a gut regulatory compound2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 201, no 1, 151-156 p.Article, review/survey (Refereed)
    Abstract [en]

    Gastric emptying is the first step in the metabolic endocrine cascade that takes place after food intake. The incretin hormones originating in the gut, particularly GLP-1, exert multiple antihyperglycaemic actions such as enhancement of glucose-dependent insulin secretion, suppression of glucagon secretion, slowing of gastric emptying with an ensuing decrease in food intake and weight loss. From extensive studies in experimental animals and humans we have found that GLP-1 also exerts a motility-inhibiting and antispasmodic effect in the gut that was verified in healthy volunteers and patients with irritable bowel syndrome (IBS). In order to further investigate the effect of GLP-1 in humans, we used the dipeptidyl peptidase-IV resistant GLP-1 analogue ROSE-010, thereby extending its biological activity. A randomized, double-blinded, prospective clinical trial was carried out in order to investigate the effect of two doses of ROSE-010 in 166 patients suffering from pain attacks of IBS. We found that injections of ROSE-010 were twice as effective as placebo in terms of total pain relief response in those affected by pain attacks due to IBS. Our results show that basal physiological research studies can be translated into clinical use. The current pharmaceutical incentive with incretin mimetics, such as GLP-1 analogues and exenatide, is an interesting development that apart from its obvious use in diabetes type 2, may also be useful in terms of gut motility-regulating effects with effects on appetite, food intake and motility disorders that may provide an opportunity to bring about new improvements in medical care.

  • 35.
    Huang, Q.
    et al.
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China..
    Wang, Q.
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China..
    Zhang, S.
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China..
    Jiang, S.
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China..
    Zhao, L.
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China..
    Yu, L.
    Zhejiang Univ, Coll Life Sci, Hangzhou, Zhejiang, Peoples R China..
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patzak, A.
    Charite, Inst Vegetat Physiol, Berlin, Germany..
    Li, L.
    Georgetown Univ, Dept Med, Div Nephrol & Hypertens, Hypertens Kidney & Vasc Res Ctr, Washington, DC USA..
    Wilcox, C. S.
    Georgetown Univ, Dept Med, Div Nephrol & Hypertens, Hypertens Kidney & Vasc Res Ctr, Washington, DC USA..
    Lai, E. Y.
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China..
    Increased hydrogen peroxide impairs angiotensin II contractions of afferent arterioles in mice after renal ischaemia-reperfusion injury2016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 218, no 2, 136-145 p.Article in journal (Refereed)
    Abstract [en]

    AimRenal ischaemia-reperfusion injury (IRI) increases angiotensin II (Ang II) and reactive oxygen species (ROS) that are potent modulators of vascular function. However, the roles of individual ROS and their interaction with Ang II are not clear. Here we tested the hypothesis that IRI modulates renal afferent arteriolar responses to Ang II via increasing superoxide (O2-) or hydrogen peroxide (H2O2). MethodsRenal afferent arterioles were isolated and perfused from C57BL/6 mice 24h after IRI or sham surgery. Responses to Ang II or noradrenaline were assessed by measuring arteriolar diameter. Production of H2O2 and O2-was assessed in afferent arterioles and renal cortex. Activity of SOD and catalase, and mRNA expressions of Ang II receptors were assessed in pre-glomerular arterioles and renal cortex. ResultsAfferent arterioles from mice after IRI had a reduced maximal contraction to Ang II (-272 vs. -42 +/- 1%, P<0.001), but retained a normal contraction to noradrenaline. Arterioles after IRI had a 38% increase in H2O2 (P<0.001) and a 45% decrease in catalase activity (P<0.01). Contractions were reduced in normal arterioles after incubation with H2O2 (-22 +/- 2 vs. -42 +/- 1%, P<0.05) similar to the effects of IRI. However, the impaired contractions were normalized by incubation with PEG catalase despite a reduced AT(1)R expression. ConclusionsRenal IRI in mice selectively impairs afferent arteriolar responses to Ang II because of H2O2 accumulation that is caused by a reduced catalase activity(.) This could serve to buffer the effect of Ang II after IRI and may be a protective mechanism.

  • 36.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Caloric restriction reduces age-related but not all-cause mortality2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no 1, 3-5 p.Article in journal (Other academic)
  • 37.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Neurohormonal interactions on the renal oxygen delivery and consumption in haemorrhagic shock-induced acute kidney injury2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 209, no 1, 11-25 p.Article, review/survey (Refereed)
    Abstract [en]

    Haemorrhagic shock is a common cause of acute kidney injury, which is a major risk factor for developing chronic kidney disease. The mechanism is superficially straightforward. An arterial pressure below the kidney's autoregulatory region leads to a direct reduction in filtration pressure and perfusion, which in turn cause renal failure with reduced glomerular filtration rate (GFR), and AKI because of hypoxia. However, the kidney's situation is further worsened by the hormonal and neural reactions to reduced perfusion pressure. There are three major systems working to maintain arterial pressure in shock: Sympathetic signaling, the renin-angiotensin-system, and vasopressin. These work to retain electrolytes and water, and to increase peripheral resistance and cardiac output. In the kidney the increased electrolyte reabsorption consumes oxygen. At the same time, at the signaling level seen in shock, all of these hormones reduces renal perfusion, and thereby oxygen delivery. This creates an exaggerated hypoxic situation that is liable to worsen the AKI. The present review will examine this mechanistic background and identify a number of areas that require further studies. At this time the ideal treatment of haemorrhagic shock appears to be slow fluid resuscitation, possibly with hyperosmolar sodium, low chloride, and no artificial colloids. From the standpoint of the kidney, renin-angiotensin system inhibitors appear fruitful for further study.

  • 38.
    Jansson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pancreatic islet blood flow during euglycaemic, hyperinsulinaemic clamp in anaesthetized rats2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, no 4, 319-324 p.Article in journal (Refereed)
    Abstract [en]

    Aims: Previous studies have demonstrated that pancreatic islet blood flow is crucially dependent on blood glucose concentration. Thus, hyperglycaemia increases and hypoglycaemia decreases islet blood perfusion, by a combination of nervous and metabolic signals. The aim of the present study was to evaluate if hyperinsulinaemia, without associated hypoglycaemia, affects islet blood flow.

    Methods: Thiobutabarbital-anaesthetized Wistar–Furth rats were subjected to an euglycaemic, hyperinsulinaemic clamp, that is they were infused for 60 min with either saline, insulin (18 mU kg−1 min−1), glucose (27 mg kg−1 min−1) or both glucose and insulin. This was followed by islet blood flow measurements with a microsphere technique.

    Results: Animals receiving only glucose doubled their blood glucose and serum insulin concentrations, whereas rats receiving only insulin had blood glucose concentrations <2 mmol L−1 and a 10-fold increase in serum insulin concentrations. Animals given simultaneous glucose and insulin had normal blood glucose concentrations but a 10-fold increase in serum insulin concentrations. Total pancreatic blood flow was unaffected in all animals. Islet blood flow was increased in hyperglycaemic and decreased in hypoglycaemic rats compared with control rats. Islet blood flow did not differ between clamped and control rats.

    Conclusions: Serum insulin concentration per se does not affect islet blood flow, whereas the ambient blood glucose concentration is of major importance in this context.

  • 39.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Insulin modulates GABA(A) receptor-mediated inhibition in rat amygdala neurons2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, 83-83 p., P39Article in journal (Other academic)
  • 40.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Insulin modulates GABAA receptor-mediated neuronal inhibition in rat hippocampus and amygdala2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, 90-90 p.Article in journal (Other academic)
  • 41.
    Jönsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Agic, Mediha Becriovic
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tveitaras, Maria
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Skogstrand, Trude
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Karlsen, Tine V.
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Lidén, Åsa
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Leh, Sabine
    Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway..
    Iversen (Late), Bjarne M.
    Univ Bergen, Inst Med, Bergen, Norway..
    Reed, Rolf K.
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Bergen, Dept Biomed, Bergen, Norway..
    C57BL/6J mice are resistant to cardiorenal syndrome during high-salt and Angiotensin II treatment compared to Balb/c because of higher oxidative stress2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, 85-85 p.Article in journal (Other academic)
  • 42. Kaufmann, J.
    et al.
    Martinka, P.
    Moede, O.
    Sendeski, M.
    Steege, A.
    Faehling, M.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gaestel, M.
    Moraes-Silva, I. C.
    Nikitina, T.
    Liu, Z. Z.
    Zavaritskaya, O.
    Patzak, A.
    Noradrenaline enhances angiotensin II responses via p38 MAPK activation after hypoxia/re-oxygenation in renal interlobar arteries2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 4, 920-932 p.Article in journal (Refereed)
    Abstract [en]

    Aim: Hypoxia and sympathetic activation are main factors in the pathogenesis of acute kidney injury (AKI). We tested the hypothesis that noradrenaline (NE) in combination with hypoxia aggravates the vasoreactivity of renal arteries after hypoxia/re-oxygenation (H/R). We tested the role of adrenergic receptors and p38 MAPK using an in vitro H/R protocol. Methods: Mouse interlobar arteries (ILA) and afferent arterioles (AA) were investigated under isometric and isotonic conditions respectively. The in vitro protocol consisted of 60-min hypoxia and control condition, respectively, 10-min re-oxygenation followed by concentration-response curves for Ang II or endothelin. Results: Hypoxia reduced the response to Ang II. Hypoxia and NE (10(-9) mol L-1) together increased it in ILA and AA. In ILA, NE alone influenced neither Ang II responses under control conditions nor endothelin responses after hypoxia. Prazosin or yohimbine treatment did not significantly influence the NE+hypoxia effect. The combination of prazosin and yohimbine or propranolol alone inhibited the effect of NE+hypoxia. BRL37344 (beta(3) receptor agonist) mimicked the NE effect. In contrast, the incubation with beta(3) receptor blocker did not influence the mentioned effect. Phosphorylation of p38 MAPK and MLC(20) was increased after H/R with NE and Ang II treatment. The selective p38 MAPK inhibitor SB202190 blocked the NE+hypoxia effect on the Ang II response. Conclusion: The results suggest an interaction of NE and hypoxia in enhancing vasoreactivity, which may be important for the pathogenesis of AKI. The effect of NE+hypoxia in ILA is mediated by several adrenergic receptors and requires the p38 MAPK activation.

  • 43.
    Kjaergaard, M.
    et al.
    Novo Nordisk AS, Dept Type Diabet Pharmacol 2, Malov, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Vet Clin & Anim Sci, DK-1870 Frederiksberg C, Denmark..
    Nilsson, Cecilia
    Uppsala University.
    Rosendal, A.
    Novo Nordisk AS, Dept Assay Technol, Malov, Denmark..
    Nielsen, M. O.
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Vet Clin & Anim Sci, DK-1870 Frederiksberg C, Denmark..
    Raun, K.
    Novo Nordisk AS, Dept Type Diabet Pharmacol 2, Malov, Denmark..
    Maternal chocolate and sucrose soft drink intake induces hepatic steatosis in rat offspring associated with altered lipid gene expression profile2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 210, no 1, 142-153 p.Article in journal (Refereed)
    Abstract [en]

    AimAccording to the World Diabetes Foundation, there is an urgent need to investigate the impact of maternal health and nutrition during pregnancy to understand the background for the accelerating incidence of obesity and type 2 diabetes. In this study, we specifically concentrated on the role of overfeeding during different developmental periods. MethodsSprague-Dawley rats were offered chow or high-fat/high-sucrose diet (chow plus chocolate and soft drink) during gestation and lactation. At birth, offspring were randomly cross-fostered within each dietary group into small and normal litter sizes until weaning, giving four dietary groups. ResultsAt postnatal day 1, offspring from high-fat/high-sucrose-fed dams were heavier and had increased hepatic triglycerides (TG), hepatic glycogen, blood glucose and plasma insulin compared with offspring from chow-fed dams. Hepatic genes involved in lipid oxidation, VLDL transport and insulin receptor were down-regulated, whereas FGF21 expression was up-regulated. Independent of postnatal litter size, offspring from high-fat/high-sucrose-fed dams aged 21days had still increased hepatic TG and up-regulated FGF21 expression, while plasma insulin started to decrease. Litter size reduction in offspring from high-fat/high-sucrose-fed dams further increased body weight and adiposity, and up-regulated genes involved in hepatic mitochondrial lipid oxidation and VLDL transport compared with all other groups. Litter size reduction did not have any impact on body weight gain and adiposity in offspring born to chow-fed dams. ConclusionOur results suggest that supplementation of chocolate and soft drink during gestation and lactation contributes to early onset of hepatic steatosis associated with changes in hepatic gene expression and lipid handling.

  • 44.
    Korol, Sergiy V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Babateen, Omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Modulation of GABAA receptor-mediated synaptic and tonic currents in the rat hippocampus by GLP-1, exendin-4 and diazepam2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, 89-90 p.Article in journal (Other academic)
  • 45.
    Korol, Sergiy V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Babateen, Omar M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA(A) receptor-mediated currents in the hippocampus are transiently enhanced by glucagon-like peptide-1 receptor (GLP-1R) agonists2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, 83-83 p., P38Article in journal (Other academic)
  • 46. Krishtal, O.
    et al.
    Maximyuk, O.
    Khmyz, V.
    Lindskog, C.
    Vukojevic, V.
    Ivanova, T.
    Rajnisz, A.
    Solecka, J.
    Lipkowski, A.
    Hauser, K.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Opioid neuropeptides make pores in plasma membrane: possible mechanism of signal transduction2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, 12-12 p.Article in journal (Other academic)
  • 47.
    Lai, En Yin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Patzak, Andreas
    Persson, A. Erik . G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Angiotensin II enhances the afferent arteriolar response to adenosine through increases in cytosolic calcium2009In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 196, no 4, 435-445 p.Article in journal (Refereed)
    Abstract [en]

     Aims: Angiotensin II (Ang II) is a strong renal vasoconstrictor and modulates the tubuloglomerular feedback (TGF). We hypothesized that Ang II at low concentrations enhances the vasoconstrictor effect of adenosine (Ado), the mediator of TGF. Methods: Afferent arterioles of mice were isolated and perfused, and both isotonic contractions and cytosolic calcium transients were measured. Results: Bolus application of Ang II (10(-12) and 10(-10)M) induced negligible vasoconstrictions, while Ang II at 10(-8) M reduced diameters by 35%. Ang II at 10(-12), 10(-10), and 10(-8) M clearly enhanced the arteriolar response to cumulative applications of Ado (10(-11) to 10(-4)M). Ado application increased the cytosolic calcium concentrations in the vascular smooth muscle, which were higher at 10(-5)M than at 10(-8)M. Ang II (10(-11) to 10(-6)M) also induced concentration-dependent calcium transients, which were attenuated by AT(1) receptor inhibition. Simultaneously applied Ang II (10(-10)M) additively enhanced the calcium transients induced by 10(-8) and 10(-5) M Ado. The transients were partly inhibited by AT(1) or A(1) receptor antagonists, but not significantly by A(2) receptor antagonists. Conclusion: A low dose of Ang II enhances Ado-induced constrictions, partly via AT(1) receptor-mediated calcium increase. Ado increases intracellular calcium by acting on A(1) but not A(2) receptors. The potentiating effect of Ang II on Ado-induced arteriolar vasoconstrictions may involve calcium sensitization of the contractile machinery, as Ang II only additively increased cytosolic calcium concentrations, while its effect on the arteriolar constriction was more than additive. The potentiating effect of Ang II might contribute to the resetting of TGF.

  • 48.
    Li, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Li, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Marx, J
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Scaling of motility speed and its temperature sensitivity in mammals representing a 5,500-fold difference in body size2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 202, no 4, 671-681 p.Article in journal (Refereed)
    Abstract [en]

    Aim: 

    The predictions of scaling of skeletal muscle shortening velocity made by A.V. Hill 60-years ago have proven to be remarkably accurate at the cellular level. The current investigation looks to extend the study of scaling of contractile speed to the level of the molecular motor protein myosin at both physiological and unphysiological low temperatures.

    Methods: 

    A single muscle cell in vitro motility assay to test myosin function, i.e. myosin extracted from short single muscle fibre segments, was used in four species representing a 5 500-fold difference in body mass (rat, man, horse and rhinoceros) at temperatures ranging from 15 to 35 °C.

    Results: 

    The in vitro motility speed increased as the temperature of the assay increased, but a more profound effect was observed on the slower isoforms, narrowing the relative differences between fast and slow myosin heavy chain (MyHC) isoforms at physiological temperature in all species. The in vitro motility speed varied according to MyHC isoform within each species: I < IIa < IIx < IIb, but the expected scaling relationship within orthologous myosin isoforms was not observed at any temperature.

    Conclusion: 

    The scaling effect of body size and limb length on shortening velocity at the muscle fibre level, i.e. the decreasing shortening velocity associated with increasing body weight and limb length, was not confirmed at the motor protein level when including mammals of very large size. Thus, other factors than myosin structure and function appear to cause this scaling effect and thin filament isoform expression or myofilament lattice spacing are forwarded as alternative underlying factors.

  • 49.
    Li, Meishan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Li, Mingxin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Marx, J O
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    There is no slowing of motility speed with increased body size in rat, human, horse and rhinoceros independent on temperature and skeletal muscle myosin isoform2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 202, no 4, 671-681 p.Article in journal (Refereed)
    Abstract [en]

    Aim:  The predictions of scaling of skeletal muscle shortening velocity made by A.V. Hill 60-years ago have proven to be remarkably accurate at the cellular level. The current investigation looks to extend the study of scaling of contractile speed to the level of the molecular motor protein myosin at both physiological and unphysiological low temperatures. Methods:  A single muscle cell in vitro motility assay to test myosin function, i.e. myosin extracted from short single muscle fibre segments, was used in four species representing a 5 500-fold difference in body mass (rat, man, horse and rhinoceros) at temperatures ranging from 15 to 35 °C. Results:  The in vitro motility speed increased as the temperature of the assay increased, but a more profound effect was observed on the slower isoforms, narrowing the relative differences between fast and slow myosin heavy chain (MyHC) isoforms at physiological temperature in all species. The in vitro motility speed varied according to MyHC isoform within each species: I < IIa < IIx < IIb, but the expected scaling relationship within orthologous myosin isoforms was not observed at any temperature. Conclusion:  The scaling effect of body size and limb length on shortening velocity at the muscle fibre level, i.e. the decreasing shortening velocity associated with increasing body weight and limb length, was not confirmed at the motor protein level when including mammals of very large size. Thus, other factors than myosin structure and function appear to cause this scaling effect and thin filament isoform expression or myofilament lattice spacing are forwarded as alternative underlying factors.

  • 50.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hagg, S.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Variation in genes in the endothelin pathway and endothelium-dependent and endothelium-independent vasodilation in an elderly population2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 208, no 1, 88-94 p.Article in journal (Refereed)
    Abstract [en]

    Aim Indirect evidences by blockade of the endothelin receptors have suggested a role of endothelin in endothelium-dependent vasodilation. This study aimed to investigate whether circulating levels of endotehlin-1 or genetic variations in genes in the endothelin pathway were related to endothelium-dependent vasodilation. Methods In 1016 seventy-year-old participants of the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (52% women), we measured endothelium-dependent vasodilation using the invasive forearm technique with acetylcholine given in the brachial artery (EDV) and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma endothelin-1 levels were measured and 60 SNPs in genes in the endothelin pathway (ECE1, EDN1, EDNRA, EDNRB) were genotyped. Results No significant associations were found between circulating endothelin levels and EDV or FMD. No single genotype was related to EDV or FMD following adjustment for multiple testing, but a genotype score for 3 SNPs (rs11618266 in EDNRB, rs17675063 in EDNRA, rs3026868 in ECE1) was significantly related to EDV (beta coefficient 0.070, 95% CI 0.0250.12, P=0.002) when adjusting for gender, systolic blood pressure, HDL and LDL cholesterol, serum triglycerides, BMI, diabetes, smoking, antihypertensive medication or statins and CRP. This score was also related to nitroprusside-induced vasodilation in the forearm. Conclusion A combination of genotypes in the endothelin pathway was related to both endothelium-dependent and endothelium-independent vasodilation in forearm resistance vessels, but not in the brachial artery in an elderly population, giving evidence for a role of the endothelin system in resistance vessel reactivity independent of major cardiovascular risk factors.

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