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  • 1.
    Atuma, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Engstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Helicobacter pylori extracts reduce gastric mucosal blood flow by a nitric oxide-independent but mast cell- and platelet-activating factor receptor-dependent pathway in rats1999In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 34, no 12, p. 1183-1189Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously shown that water extracts from Helicobacter pylori reduce gastric mucosal blood flow by approximately 15%. It has also been suggested that H. pylori can inhibit endogenous nitric oxide (NO) biosynthesis. Our aim was to examine whether the reduction in blood flow induced by H. pylori is the direct consequence of an NO synthase inhibition and the possible involvement of mast cell degranulation.

    METHODS: A water extract was produced from wildtype strain 88-23. The extract was applied on the exteriorized gastric corporal mucosa in inactin-anesthetized rats, after removing as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured with laser-Doppler flowmetry.

    RESULTS: In rats pretreated with the NO synthase inhibitor N-nitro-L-arginine there was a 19% +/- 6% reduction in blood flow 40 min after application of the extract, and a 27% +/- 9% reduction after another 20 min with saline. The reduction was abolished by concomitant pretreatment with the mast cell stabilizer ketotifen or the platelet-activating factor (PAF) receptor antagonist WEB2086.

    CONCLUSION: The reduction in mucosal blood flow induced by the extract was probably mediated through an acute inflammatory response involving mast cell degranulation with consequent PAF secretion. The effect on blood flow was not the result of a decrease in vascular tone due to an inhibition of endogenous NO biosynthesis.

  • 2.
    Atuma, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Strugala, V
    Allen, A
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    The adherent gastrointestinal mucus gel layer: thickness and physicalstate in vivo2001In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 280, p. G922-G929Article in journal (Refereed)
    Abstract [en]

    Divergent results from in vitro studies on the thickness and appearance of the gastrointestinal mucus layer have previously been reported. With an in vivo model, we studied mucus gel thickness over time from stomach to colon. The gastrointestinal tissues of Inactin-anesthetized rats were mounted luminal side up for intravital microscopy. Mucus thickness was measured with a micropipette before and after mucus removal by suction. The mucus layer was translucent and continuous; it was thickest in the colon (∼830 μm) and thinnest in the jejunum (∼123 μm). On mucus removal, a continuous, firmly adherent mucus layer remained attached to the epithelial surface in the corpus (∼80 μm), antrum (∼154 μm), and colon (∼116 μm). In the small intestine, this layer was very thin (∼20 μm) or absent. After mucus removal, there was a continuous increase in mucus thickness with the highest rate in the colon and the lowest rate in the stomach. In conclusion, the adherent gastrointestinal mucus gel in vivo is continuous and can be divided into two layers: a loosely adherent layer removable by suction and a layer firmly attached to the mucosa.

  • 3.
    Atuma, Christer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    Gastrointestinal mucosal protective mechanisms: Mudolatory effects of Heliobacter pyroli on the gastric mucus gel barrier and mucosal blood flow in vivo2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The gastrointestinal mucus gel layer and blood flow are two important mechanisms for protection at the pre-epithelial and sub-epithelial levels, respectively. Helicobacter pylori might circumvent these mechanisms and elicit a chronic inflammatory response with consequent ulcers in the stomach and duodenum. In this thesis, the physical state and properties of the adherent mucus gel layer was studied from the stomach to colon. Furthermore, the acute and chronic effects of H. pylori on the integrity of the mucus gel layer and mucosal blood flow were studied in the anesthetized rat.

    A translucent mucus gel covers all studied segments of the gastrointestinal tract during fasting conditions, with the thickest layers in the colon and ileum. Carefully applied suction revealed that the mucus gel was a multi-layered structure comprising a firmly adherent layer covering the mucosa, impossible to remove, and a loosely adherent upper layer. The firmly adherent layer was thick and continuous in the corpus (80μm), antrum (154μm) and colon (116μm), but thin (<20μm) and discontinuous in the small intestine.

    Following mucus removal, a rapid renewal of the loosely adherent layer ensued. The highest rate was observed in the colon with intermediate values in the small intestine. Mucus renewal in the stomach was attenuated on acute luminal application of water extracts from H. pylori (HPE). In animals with a chronic H. pylori infection the mucus renewal rate was unaffected, but the total gastric mucus gel thickness was reduced and the mucus secretory response to luminal acid (pH1) attenuated in the antrum.

    HPE from type I strains acutely reduced corporal mucosal blood flow, measured with laser-Doppler flowmetry, by approximately 15%. The reduction in blood flow was mediated by a heat stable factor other than VacA and CagA. Inhibition of endogenous nitric oxide production with Nω-nitro-l-arginine augmented the decrease. However, ketotifen, a mast cell stabilizer, completely attenuated the effect of the extract as did the platelet activating factor (PAF) receptor-antagonist, WEB2086, thus depicting a detrimental role for the microvascular actions of PAF.

  • 4.
    Atuma, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Engstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Extracts of Helicobacter pylori reduce gastric mucosal blood flow through a VacA- and CagA-independent pathway in rats1998In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 33, no 12, p. 1256-1261Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Helicobacter pylori may interfere with gastroduodenal protective mechanisms. Such effects could be due to a direct interaction with gastric epithelial cells but also to the action of a wide range of secreted and membrane-bound virulence factors. Our aim was to study the acute effects of water extracts produced from H. pylori on gastric mucosal blood flow and acid secretion and to relate them to VacA and CagA activity.

    METHOD: Extracts were produced from strains 88-23 and A5, both wild type; A5VacA, an isogenic mutant lacking expression of the vacuolating cytotoxin (VacA) and the immunodominant antigen (CagA); and Escherichia coli strain ATCC-25922. Bacterial extracts were applied on the exteriorized gastric corporal mucosa in inactin-anaesthetized rats after removal of as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured by means of laser-Doppler flowmetry.

    RESULTS: All H. pylori extracts, including the extract from 88-23 heated to 100 degrees C for 30 min, significantly reduced blood flow by 15%-19%, whereas E. coli had no significant effect on blood flow.

    CONCLUSION: A factor or a combination of factors, other than VacA and CagA released from H. pylori, might compromise the natural defence of the gastric corporal mucosa by reducing mucosal blood flow. The factor is heat-stable and lacking or less potent in E. coli.

  • 5.
    Carlsson, Hans-Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Persdotter Hedlund, Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Fries, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hau, Jann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Purification, characterization, and biological compartmentalization of rat fetal antigen 12000In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 63, no 1, p. 30-33Article in journal (Refereed)
    Abstract [en]

    This study has established the rat as an animal model for the analysis of the biological role of fetal antigen 1 (FA1), a protein previously described in humans and mice. FA1 was purified from rat amniotic fluid by immunospecific affinity chromatography. Immunochemical identity between mouse and rat FA1 was established by crossed tandem immunoelectrophoresis. Molecular size was analyzed by mass spectrometry (33 kDa). The amino acid composition was determined, and the amino acid sequence was analyzed. The overall amino acid composition and sequence of the 28 first N-terminal amino acids were identical to the corresponding parts of rat preadipocyte factor 1 and rat adrenal zone glomerulosa protein. Extensive sequence similarity was found between rat and mouse FA1 (86%) and between rat and human FA1 (82%). The concentration of FA1 in fetal serum, maternal serum, urine, and amniotic fluid in rats was determined using an ELISA. The highest concentrations were found in fetal serum and amniotic fluid around Day 18 of pregnancy. This is the first report on the physicochemical characteristics and compartmentalization of rat FA1.

  • 6.
    Clemedson, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    An Experimental Study on Air Blast Injuries1949Doctoral thesis, monograph (Other academic)
  • 7.
    Farah, Idle Omar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    Immunopathogenesis of schistosomiasis mansoni: Immunity and pathology in a primary and a secondary infection following chemotherapy in the mouse and the baboo models2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes a series of experiments aimed at elucidating the mechanisms ofimmunity and pathology elicited by both a primary infection and a reinfection exposure toSchistosoma mansoni following chemotherapy. The effects of a single large cercarial doseand a cumulatively equivalent dose, administered as multiple small doses are compared. Inaddition, the suitability of two animal models, a murine (BALB/c mice) and a non-humanprimate (Olive baboons, Papio cynocephalus anubis) for this purpose is evaluated. Duringthe primary infection, single-dose infected (SI) baboons developed more severe clinicaldisease than the multiple-dose infected (MI) group. Hepatic granulomata developed morerapidly and modulated more slowly in the SI group than in the MI group. Intestinal lesions inthe infected baboons included smooth muscle hypertrophy, villous atrophy and goblet cellhyperplasia, which were all less severe in baboons previously immunised with irradiatedcercariae. High tissue eosinophilia and recruitment of giant cells was observed in modulatingbaboon granulomata. By contrast, fibroblasts and collagen around the schistosome eggs werethe features of modulating mouse granulomata. In both animal models, reinfection followingchemotherapy resulted in reduced morbidity compared to a primary infection and a primaryMI dose elicited a T helper (Th) 2 cell associated immune response on reinfection. A primarySI dose in mice, however, led to a dominant Th1 response. Baboons exposed to multipleinfections, both prior to and following chemotherapy, developed peri-portal fibrosis. Insummary, i) variation in cercarial exposure contributes to the heterogeneity of the immuneresponse and morbidity ii) although the consequences of reinfection exposures are milder, they may be associated with increased risk for the development of hepatic fibrosis and iii)regarding the pathogenesis of natural schistosome infections, particularly repeated infections,the baboon is a better model than the mouse.

  • 8.
    Guhad, Faisal Abdi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    Development and validation of a localized murine candidiasis model: The pathogenesis, chemotheraphy and defense mechanisms to Candida mastitis in the lactating mouse1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A murine model of localized candidiasis (mastitis) was developed. The model was analyzed withrespect to its discriminative abilities through investigation of the virulence properties of C.albicans mutant strains compared with the wild-type parental strain. Further validation of themodel was undertaken by assessment of pathogenesis, chemotherapy (amphotericin B andfluconazole) and complement activation using immunocompetent BALB/c mice, SCID andathymic nude mice. Six to eight week old mice were time mated. The pups were allowed to suckleup to day five post partum, at which time the lactating glands were inoculated with between 104 to109 cells of Candida. The animals were euthanized after 1-6 days of infection. The mammaryglands and several other organs were evaluated histopathologically. In the chemotherapy studies,the mammary glands were homogenized and fungal burden determined through culture of differentdilutions of the homogenate. Except in the very high inocula dose, the fungi were confined to themammary gland tissues. The infection remained localized and was most severe in SCID, followedby immunocompetent and athymic nude mice, in that order. The severity of pathological changes,which consisted of infiltration with neutrophils, necrosis and abscess formation, was exacerbatedby increasing the number of cells and/or the duration of infection in the untreated control animals.Animals infected with virulence factor knock-out strains showed reduced or no lesions while themajority of the animals infected with the wild-type strains showed severe lesions. In theamphotericin B treated animals, only mild pathological changes were seen compared to theinfected controls. Fluconazole treatment was ineffective in the treatment of mastitis. Complementfactor C3c levels were elevated and correlated to the severity of inflammation in all theexperiments and were significantly reduced by amphotericin B but not by fluconazole treatment.Conclusions: i) the murine mycotic mastitis is a discriminative model of localized candidiasis ii)severity of infection is dose- and duration-dependent iii) antifungal drugs can significantly reducefungal burden in the mammary gland and iv) there are other immune mechanisms that protect miceagainst dissemination of infection than T and B cell immunity.

  • 9.
    Gutiérrez, Antonio M.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    Studies of nucleotide receptors-induced calcium response in glomerular mesangial cells and afferent arterioles1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    It is known that intracellular calcium concentration ([Ca2+]i) changes in rat glomerular mesangial cells (GMC) and rabbit afferent arterioles (AA) in response to extracellular nucleotides. We studied the nucleotide-induced calcium response in cultured GMC and AA. We characterized the response of GMC to extracellular nucleotides at the single cell level and in first passage cells. GMC basal [Ca2+]i was always between 70-90 nM. The cells responded to 0.1 mM ATP or UTP with a biphasic [Ca2+]i increase. The order of efficacy of nucleotide agonists was UTP = ATP > ATPγS > ADP = 2MeS-ATP, Adenosine, AMP and β,γ-Me-ATP had no effect. Consecutive ATP challenges induced receptor desensitization. Stimulation of PKC (PMA) abolished responses to ATP or UTP. Inhibition of PKC (chelerythrine) in contrast prevented desensitization. The desensitization was reversed by 4-min incubation with PDGF-BB or insulin. Theinfluence of protein phosphatases (PP) on receptor desensitization and on insulin-induce resensitization was studied using the PP inhibitors okadaic acid and cypermethrin. Internalization of nucleotides receptors was blocked with hyperosmotic sucrose solution. The calcium response of freshly dissected AA to adenosine, ATP and UTP was characterized in defined proximal and distal AA regions.

    The results show that: (i) GMC express P2Y2 receptor subtype. (ii) Desensitization is mediated by PKC and resensitization is modulated by growth factors. (iii) PP2B antagonizes desensitization. PP1 is involved in the insulin-induced resensitization. Internalization is a prerequisite for resensitization. (iv) P1 and P2X receptors are present along AA and both, mediate calcium mobilization with no difference in distribution in the proximal and distal AA segments.

  • 10.
    Holm-Rutili, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Effects of omeprazole on gastric mucosal microcirculation and acid secretion in the rat1987In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 92, no 3, p. 716-723Article in journal (Refereed)
    Abstract [en]

    Omeprazole, a potent long-acting inhibitor of gastric acid secretion that exerts its inhibitory action by direct blocking of the H+, K+-adenosine triphosphatase in the parietal cells, was either applied topically to the solution bathing the exposed mucosa of the test rats or administered intravenously as a bolus injection. The superficial mucosal vessels were monitored on a television screen through a microscope and videorecorded for off-line analysis of red cell velocities and vessel diameters, from which blood flow was calculated. Intravenous omeprazole (5 or 10 mumol/kg) totally abolished the basal secretion 15-25 min after injection, with a parallel decrease in blood flow of approximately 25% for both doses. Omeprazole, 5 mumol/kg, given intravenously to rats stimulated with pentagastrin (20 micrograms/kg X h) significantly inhibited the stimulated acid output, but the blood flow was not significantly decreased. Topical application of omeprazole (2.5 mM in 6 ml) significantly increased blood flow (approximately 15%) while in contact with the mucosa both in the resting and in the pentagastrin (20 micrograms/kg X h)-stimulated situations. However, 10-20 min after the application period, blood flow was restored to the values before application of omeprazole and the acid output was significantly decreased. The results indicate that omeprazole exerts only minor influences on the gastric mucosal microcirculation in spite of its potent acid-inhibitory effect.

  • 11.
    Holm-Rutili, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Effects of prostaglandin E1, E2 and 16,16-dimethyl-E2 on gastric mucosal microcirculation and basal acid output in the rat1986In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 127, no 3, p. 313-321Article in journal (Refereed)
    Abstract [en]

    The effects of prostaglandins E1 (PGE1), E2 (PGE2) and 16,16-dimethyl-E2 (16,16-dm-PGE2) on the gastric mucosal microcirculation and (spontaneous) acid output were studied in anaesthetized rats. The superficial mucosal vessels were monitored on a TV screen using a microscope, TV camera and videorecorder for off-line analysis of red cell velocities (VRBC) and vessel diameters, from which the blood flow (QRBC) was calculated. The prostaglandins were either applied topically to the solution bathing the exposed mucosa or administered intravenously as a continuous infusion. Topical application of PGE1 (0.5 or 5 micrograms ml-1), PGE2 (5 or 50 micrograms ml-1) or 16,16-dm-PGE2 (0.005, 0.05 or 0.5 microgram ml-1) increased VRBC dose-dependently without altering acid output, except for the highest dose of PGE2 (50 micrograms ml-1) which inhibited acid output. The latter occurred in spite of a seven- to eight-fold increase in VRBC. Mucus secretion (evidenced by an impaired resolution of the TV image) also increased during topical application of the prostaglandins especially at higher doses. Intravenous PGE1, PGE2 (2.0 micrograms kg-1 min-1) or 16,16-dm-PGE2 (0.02 microgram kg-1 min-1) caused an initial and transient (5-10 min) fall in systemic arterial blood pressure and a decrease in VRBC and acid output. Intravenous 16,16-dm-PGE2 in a dose which did not affect secretion or systemic arterial blood pressure (0.002 microgram kg-1 min-1) still significantly reduced VRBC. Thus, topically applied PGE1, PGE2 or 16,16-dm-PGE2 dose-dependently increase VRBC while intravenous administration of the same prostaglandins reduce VRBC.

  • 12.
    Holm-Rutili, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Berglindh, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Pentagastrin and gastric mucosal blood flow1986In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 250, no 5 Pt 1, p. G575-G580Article in journal (Refereed)
    Abstract [en]

    The effect of pentagastrin on mucosal microcirculation was studied in rats by use of intravital microscopy. The superficial mucosal vessels were videorecorded for off-line analysis of red cell velocities (VRBC) and vessel diameters, from which blood flow (QRBC) was calculated. Resting mucosal blood flow calculated from single microvascular flow data, and vessel distribution was 40 ml X min-1 X 100 g-1. Pentagastrin infused intravenously in a dose of 20 micrograms X kg-1 X h-1 resulted in submaximal acid secretion (approximately 60%) and a significant increase in QRBC by 47 +/- 14%. When given in a dose of 96 micrograms X kg-1 X h-1 iv, it resulted in maximal acid secretion and an increase in QRBC by 36 +/- 14%. In another series of experiments the results of QRBC measurements during infusion of pentagastrin (20 micrograms X kg-1 X h-1 iv) were compared with those of aminopyrine (AP) clearance or laser-Doppler flowmetry (LDF) in the same animals. Gastric mucosal blood flow determined by [14C]AP clearance increased by 309 +/- 115%, whereas QRBC increased by 34 +/- 11%. When determined by LDF, blood flow increased by 41 +/- 22%, a value similar to the increase in QRBC (50 +/- 19%). Thus, the percent increase in blood flow during pentagastrin infusion estimated by AP clearance was considerably higher than that observed by either direct microvascular measurements or by LDF.

  • 13.
    Holm-Rutili, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Öbrink, Karl Johan
    Rat gastric mucosal microcirculation in vivo1985In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 248, no 6 Pt 1, p. G741-G746Article in journal (Refereed)
    Abstract [en]

    The superficial gastric mucosal microcirculation was observed microscopically by transillumination in the anesthetized rat. The vessels surrounding the gastric crypts were monitored on a television screen through a microscope and the pictures stored on a videotape for off-line analysis of red cell velocity (VRBC) and vessel diameter. From these measurements microvascular volume flows were calculated. VRBC reached steady values after 1-4 h (mean 2 h) and showed a regular pulsatile flow (4-7 cycles/min) in most experiments. Acid output was measured at regular intervals; 50% of the rats showed no spontaneous acid output, but the others secreted up to 100 mu eq/h. The microvessels in the superficial mucosa were classified into three orders according to their branching hierarchy and relative dimensions, and their distribution per unit mass was estimated. VRBC and volume flow were shown to decrease in the successive orders of the microvessels. Calculation of organ blood flow from microvascular flow data and vessel distribution gave values (21 ml.min-1.100 g tissue-1) that agree with earlier reported values. A higher flow velocity was detected in rats with spontaneous acid output than in those without, but there was a poor correlation between the magnitude of the acid output and VRBC. Pentagastrin (96 micrograms.kg-1.h-1) induced a significant increase in both blood flow and acid secretion. Results from this study indicate that this experimental model is potentially useful for studies of the correlation between acid secretion and mucosal blood flow.

  • 14.
    Näsman, Johnny
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    Alpha-2 Adrenergic Receptors and Signal Transduction: Effector Output in Relation to G-Protein Coupling and Signalling Cross-Talk2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The alpha-2 adrenergic receptor (α2-AR) subfamily includes three different subtypes, α2A-, α2B- and α2C-AR, all believed to exert their function through heterotrimeric Gi/o-proteins. The present study was undertaken in order to investigate subtype differences in terms of cellular response and to explore other potential signalling pathways of α2-ARs.

    Evidence is provided for a strong Gs-protein coupling capability of the α2B-AR, leading to stimulation of adenylyl cyclase (AC). The difference between the α2A- and α2B-AR subtypes, in this respect, was shown to be due to differences in the second intracellular loops of the receptor proteins. Substitution of the second loop in α2A-AR with the corresponding domain of α2B-AR enrolled the chimeric α2A2B receptor with functional α2B-AR properties. Dual Gi and Gs coupling can have different consequences for AC output. Using coexpression of receptors and G-proteins, it was shown that the ultimate cellular response of α2B-AR activation is largely dependent on the ratio of Gi- to Gs-protein amounts in the cell. Also Gi- and Go-proteins appear to have different regulatory influences on AC. Heterologous expression of AC2 together with Gi or Go and the α2A-AR resulted in receptor-mediated inhibition of protein kinase C-stimulated AC2 activity through Go, whereas activation of Gi potentiated the activity.

    α2-ARs mobilize Ca2+ in response to agonists in some cell types. This response was shown to depend on tonic purinergic receptor activity in transfected CHO cells. Elimination of the tonic receptor activity almost completely inhibited the Ca2+ response of α2-ARs.

    In conclusion, α2-ARs can couple to multiple G-proteins, including Gi, Go and Gs. The cellular response to α2-AR activation depends on which receptor subtype is expressed, which cellular signalling constituents are engaged (G-proteins and effectors), and the signalling status of the effectors (dormant or primed).

  • 15.
    Odlind, Cecilia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    The Role of Dopamine-Metabolising Enzymes in Renal Sodium Handling. An Experimental Study in vivo2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Dopamine (DA) has been shown to act as an intrarenal natriuretic hormone and defects in the renal DA system have been associated with some forms of hypertension. How the DA activity is upregulated durin- increased sodium intake is, however, unknown. The present study addressed some aspects of the regulation and execution of DA-mediated natriuresis, with the main focus on the role of the DA-metabolising enzyme catechol-O-methyltransferase (COMT).

    COMT inhibition results in DA-induced natriuresis. The natriuretic response is mediated via the D1-like receptor and not the D2-like receptor and does not involve changes in renal haemodynamics, pointing to an effect on tubular sodium transport. MAO inhibition does not after sodium excretion. Furthermore, specific renal cortical COMT activity is reduced during partly D1-like receptor-mediated natriuresis, whereas MAO activity remains unchanged. The results suggest that the importance of MAO is negligible compared to COMT in regulating DA- mediated natriuresis in the rat. Systemic administration of a DA precursor only results in a modest increase in urinary sodium excretion in spite of a large increase in urinary DA excretion. These results indicate that DA metabolism is important in sodium homeostasis and that intrarenal DA activity is more likely regulated via DA metabolism and not primarily through a change in the systemic availability of the DA precursor. The natriuretic and haemodynamic effects of an elevation in DA activity were shown to depend on the route by which the elevation occurred. Intrarenally produced DA does not influence haemodynamics, whereas a DA agonist given systematically elicits an increase in cortical and outer medullary blood flow via vascular D1-like receptors. Cortical and outer medullary oxygen tension was not measurably altered during DA- induced natriuresis. In genetically modified mice it was shown that a reduced or absent COMT activity results in an inability to increase the renal DA activity and to produce normal natriuresis in response to sodium loading.

    In summary, the results from the present study suggests that COMT activity in the kidney plays an important role in the DA-mediated regulation of renal sodium excretion in response to sodium loading in rats and mice.

  • 16.
    Persdotter Hedlund, Gabriella
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Carlsson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Shieck, Elise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Nilsson, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Lundblad, Cornelia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Arons, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Iversen, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Looman, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Jensen, H.E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Hau, Jann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Fetal antigen 1 (FA1) in the adult rat adrenal gland, ovary and pituitary gland2003In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 17, no 1, p. 1-4Article in journal (Refereed)
    Abstract [en]

    Fetal antigen 1 (FA1) is a circulating glycoprotein containing six epidermal growth factor (EGF)-like repeats. FA1's larger membrane-bound precursor is defined by the cDNAs referred to as either human delta-like (dlk) or human adrenal specific cDNA, pG2. In rodents FA1 has also been studied under the names of preadipocyte factor 1 (Pref-1), and zona glomerulosa-specific factor (ZOG). FA1 is abundantly expressed in fetal tissues, but in the mature cells of the adult organism the tissue presence of the protein seems to be restricted to neuroendocrine tissues. The present study demonstrates FA1 localisation in endocrine tissues of the adult female rat in which the protein was found present in the medulla and the zona glomerulosa of the cortex of the adrenal glands, in the pars distalis of the adenohypophysis, and in the ovarian granulosa lutein cells. No staining was found in the pancreas, which is in contrast to what has been described in the human.

  • 17.
    Pietras, Kristian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Östman, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Buchdunger, Elisabeth
    Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland.
    Reed, Rolf K
    Department of Physiology, University of Bergen, N-5009 Bergen, Norway .
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors.2001In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 61, no 7, p. 2929-2934Article in journal (Refereed)
    Abstract [en]

    Most solid malignancies display interstitial hypertension and a poor uptake of anticancer drugs. Platelet-derived growth factor (PDGF) and the cognate tyrosine kinase receptors are expressed in many tumors. Signaling through PDGFbeta receptors was shown recently to increase interstitial fluid pressure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this study, we show that treatment with the selective PDGF receptor kinase inhibitor, STI571, formerly known as CGP57148B, decreased the interstitial hypertension and increased capillary-to-interstitium transport of 51Cr-EDTA in s.c. growing rat PROb colonic carcinomas. Furthermore, treatment with an antagonistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension in these tumors. PDGFbeta receptors were expressed in blood vessels and stromal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biology, although similar effects of PDGF on IFP have been demonstrated previously in the dermis. The data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy.

  • 18.
    Samuelsson-Almén, Maria
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    Aspects of aqueous humor dynamics: Studies in vivo and in vitro1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The purpose of the present investigation was to study the effects of PGF-l-isopropylester, some neuropeptides, and pharmacological agents on aqueous humor dynamics and intraocular pressure (IOP) in vivo and on adenylate cyclase activity in the nonpigmented ciliary epithelium (NPE) in vitro.

    Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) caused a dose-dependent increase in cAMP formation, indicating that the NPE contains receptors for PACAP and VIP coupled to adenylate cyclase activation. The increase in cAMP formation caused by dopamine and the D1-receptor agonist fenoldopam was blocked by the D1-receptor antagonist SCH23390, indicating coupling to receptors belonging to the D1-receptor subfamily.

    Intracameral (i.c.) administration of terbutaline, VIP, and atrial natriuretic peptide (ANF) caused an increase in aqueous humor flow (AHF) by 100%, 50%, and 50%, respectively. Dopamine and fenoldopam i.c., however, had no clear-cut effect on AHF, probably because of the complex pharmacology, which involves both stimulatory andinhibitory effects.

    The effect on AHF by terbutaline (i.v. and i.c.) and by VIP (i.v.) was abolished by the β-receptor antagonist timolol, indicating involvement of β-receptor activation. However, the effect of VIP i.c. was unaffected by timolol i.v., suggesting that VIP i.c. stimulates AHF through local effects on the ciliary epithelium, probably via VIPreceptors. ANF given i.v. increased both basal and terbutaline-stimulated AHF, but the mechanism involved in the stimulation of AHF remains unclear.

    PGF-1 -isopropylester decreased IOP and increased uveoscleral outflow in the treated eye. Pilocarpine simultaneously prevented the drop in IOP and abolished the increase in uveoscleral outflow. There was no difference between eyes threated with PGF and control eyes after systemic pretreatment with atropine. Taken together, these results indicate that PGF decreases IOP by increasing uveoscleral outflow.

  • 19.
    Suleman, Mbaruk Abdalla
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    Studies on stress in African green monkeys (Cercopithecus aethiops): Stress associated cortisol and prolactin levels, lymphocyte modulation and pathological changes in adrenal cortex, stomach and hippocampus in the African green monkey (C. aethiops)1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    African green monkeys (AGMs) are highly susceptible to captivity-induced stress. An investigation of spontaneous deaths of laboratory confined AGMs at the Institute of Primate Research, Nairobi, Kenya over a period of 7.5 years documented mild to severe gastric mucosal erosions and ulcers in 83 of 260 (32%) necropsies. The lesions numbered between one and 100 and were distributed mainly in the body and fundus of the stomach. Singly housed animals were more frequently affected than group housed individuals. Fourteen monkeys suffering from gastric ulcers showed microscopic changes in the brain. The neural degeneration was prominent in the Cornu Ammonis 1 cell field (CA 1) and CA3 regions and was characterised by shrinkage, disarrangement and loss of the pyramidal neurones. The adrenal cortex of the retrospective cases showed a moderate degree of hyperplasia. Prospective studies in wild caught AGMs revealed that acute gastric lesions developed as early as day one after capture and bilateral adrenal gland enlargement was prominent seven days post-capture No histo-pathological brain changes were found in this group of animals. The mean width of adrenal cortices in the captured monkeys (stressed) measured 1048 µm compared to the mean of 813 µm in resting wild AGMs euthanised by a rifle shot. The hyperplasia of the cortex correlated with high plasma cortisol levels in the affected animals. Mean plasma cortisol levels in resting wild monkeys were 391 nmol/L and increased sharply one day after capture to over 1000 nmol/L. The mean concentrations in singly housed monkeys were 838 nmol/L at 45 days and remained over 700 nmol/L at six months. Lymphocyte immunocompetence showed a negative correlation with the plasma cortisol concentrations. The stimulation indices indicated that the lymphocytes were suppressed as the monkeys were confined for a prolonged period. Mean plasma prolactin concentrations were between 133 and 292 mIU/L, in singly housed monkeys on day 1 and 45 respectively. The mean concentrations decreased to 132 mIU/L at six months. The pathological changes in the adrenal glands, the stomach mucosa and the brain were attributed to stress resulting from long term confinement of the monkeys especially in individual housing. This study demonstrates that i) AGMs are very sensitive animal models of stress research ii) lenient capture techniques are necessary and iii) conscientious care and husbandry are essential for ethical and scientific reasons because this species is highly susceptible to environmental stress.

  • 20.
    Torrång, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Gut, Allan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Holm-Rutili, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Öbrink, K arl Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    A probabilistic approach for evaluating a technique for an indirect monitoring of the capillary blood flow to the gastric parietal cells1987In: Bulletin of Mathematical Biology, ISSN 0092-8240, E-ISSN 1522-9602, Vol. 49, no 2, p. 171-185Article in journal (Refereed)
    Abstract [en]

    The superficial capillary network of the gastric mucosa can be monitored for red blood cell velocity measurements by a microscopic technique. This network, however, reflects the blood flow in capillaries of more physiological interest, namely those passing by the acid-producing cells and emptying into the superficial network. It is, however, not possible to study these capillaries directly and therefore the problem is to determine in what way and to what degree blood flow measurements in the superficial network reflect the capillary flow of interest. A probabilistic approach where the movements of the red blood cells have been analysed, gives indications of determinable relations between observations on the superficial network flow and the flow passing the acid-producing cells.

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