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Persson, Erik
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Publications (10 of 63) Show all publications
Guimaraes, D. D., Cruz, J. C., Carvalho-Galvao, A., Zhuge, Z., Marques, S. M., Naves, L. M., . . . Carlstrom, M. (2019). Dietary Nitrate Reduces Blood Pressure in Rats With Angiotensin II-Induced Hypertension via Mechanisms That Involve Reduction of Sympathetic Hyperactivity. Hypertension, 73(4), 839-848
Open this publication in new window or tab >>Dietary Nitrate Reduces Blood Pressure in Rats With Angiotensin II-Induced Hypertension via Mechanisms That Involve Reduction of Sympathetic Hyperactivity
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2019 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 73, no 4, p. 839-848Article in journal (Refereed) Published
Abstract [en]

Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)-induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+ L-NAME treatment-induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of AT 1 Rs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of AT 1 Rs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2019
Keywords
angiotensin II, blood pressure, hypertension, kidney, nitric oxide, sodium nitrate, sympathethic activity
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-387561 (URN)10.1161/HYPERTENSIONAHA.118.12425 (DOI)000469351200012 ()30712424 (PubMedID)
Funder
Swedish Research Council, 2016-01381Swedish Heart Lung Foundation, 20180568 20170124
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Wei, J., Zhang, J., Jiang, S., Wang, L., Persson, A. E. & Liu, R. (2019). High-Protein Diet-Induced Glomerular Hyperfiltration Is Dependent on Neuronal Nitric Oxide Synthase beta in the Macula Densa via Tubuloglomerular Feedback Response. Hypertension, 74(4), 864-871
Open this publication in new window or tab >>High-Protein Diet-Induced Glomerular Hyperfiltration Is Dependent on Neuronal Nitric Oxide Synthase beta in the Macula Densa via Tubuloglomerular Feedback Response
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2019 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 74, no 4, p. 864-871Article in journal (Refereed) Published
Abstract [en]

It is well known that high protein intake increases glomerular filtration rate. Evidence from several studies indicated that NO and tubuloglomerular feedback (TGF) mediate the effect. However, a recent study with a neuronal NO synthase-alpha knockout model refuted this mechanism and concluded that neither neuronal NO synthase nor TGF response is involved in the protein-induced hyperfiltration. To examine the discrepancy, this study tested a hypothesis that neuronal NO synthase-beta in the macula densa mediates the high-protein diet-induced glomerular hyperfiltration via TGF mechanism. We examined the effects of high protein intake on NO generation at the macula densa, TGF response, and glomerular filtration rate in wild-type and macula densa-specific neuronal NO synthase KO mice. In wild-type mice, high-protein diet increased kidney weight, glomerular filtration rate, and renal blood flow, while reduced renal vascular resistance. TGF response in vivo and in vitro was blunted, and NO generation in the macula densa was increased following high-protein diet, associated with upregulations of neuronal NO synthase-beta expression and phosphorylation at Ser1417. In contrast, these high-protein diet-induced changes in NO generation at the macula densa, TGF response, renal blood flow, and glomerular filtration rate in wild-type mice were largely attenuated in macula densa-specific neuronal NO synthase KO mice. In conclusion, we demonstrated that high-protein diet-induced glomerular hyperfiltration is dependent on neuronal NO synthase beta in the macula densa via TGF response.

Keywords
diet, high-protein, glomerular filtration rate, nitric oxide synthase type I
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-395431 (URN)10.1161/HYPERTENSIONAHA.119.13077 (DOI)000486010100021 ()31422689 (PubMedID)
Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23Bibliographically approved
Al-Mashhadi, A. N., Checa, A., Wåhlin, N., Nevéus, T., Fossum, M., Wheelock, C. E., . . . Carlström, M. (2018). Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative stress following surgical correction of hydronephrosis in children. Pediatric nephrology (Berlin, West), 33(4), 639-649
Open this publication in new window or tab >>Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative stress following surgical correction of hydronephrosis in children
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2018 (English)In: Pediatric nephrology (Berlin, West), ISSN 0931-041X, E-ISSN 1432-198X, Vol. 33, no 4, p. 639-649Article in journal (Refereed) Published
Abstract [en]

Objective Recent clinical studies have suggested an increased risk of elevated arterial pressure in patients with hydronephrosis. Animals with experimentally induced hydronephrosis develop hypertension, which is correlated to the degree of obstruction and increased oxidative stress. In this prospective study we investigated changes in arterial pressure, oxidative stress, and nitric oxide (NO) homeostasis following correction of hydronephrosis.

Methods Ambulatory arterial pressure (24 h) was monitored in pediatric patients with hydronephrosis (n = 15) before and after surgical correction, and the measurements were compared with arterial pressure measurements in two control groups, i.e. healthy controls (n = 8) and operated controls (n = 8). Markers of oxidative stress and NO homeostasis were analyzed in matched urine and plasma samples.

Results The preoperative mean arterial pressure was significantly higher in hydronephrotic patients [83 mmHg; 95% confidence interval (CI) 80–88 mmHg] than in healthy controls (74 mmHg; 95% CI 68–80 mmHg; p < 0.05), and surgical correction of ureteral obstruction reduced arterial pressure (76 mmHg; 95% CI 74–79 mmHg; p < 0.05). Markers of oxidative stress (i.e., 11- dehydroTXB2, PGF2α, 8-iso-PGF2α, 8,12-iso-iPF2α-VI) were significantly increased (p < 0.05) in patients with hydronephrosis compared with both control groups, and these were reduced following surgery (p < 0.05). Interestingly, there was a trend for increased NO synthase activity and signaling in hydronephrosis, which may indicate compensatory mechanism(s).

Conclusion This study demonstrates increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which can be restored to normal levels by surgical correction of the obstruction. Once reference data on ambulatory blood pressure in this young age group become available, we hope cut-off values can be defined for deciding whether or not to correct hydronephrosis surgically.

Keywords Blood pressure . Hydronephrosis . Hypertension . Nitric oxide . Oxidative stress . Ureteral obstruction 

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Blood pressure, Hydronephrosis, Hypertension, Nitric oxide, Oxidative stress, Ureteral obstruction
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-337796 (URN)10.1007/s00467-017-3848-4 (DOI)000427901900012 ()29196979 (PubMedID)
Funder
Swedish Research Council, 2016-01381 MC 65X-03522-43-3 AEGPSwedish Heart Lung Foundation, 20140448The Karolinska Institutet's Research Foundation
Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2019-11-11Bibliographically approved
Al-Mashhadi, A., Häggman, M., Läckgren, G., Ladjevardi, S., Nevéus, T., Stenberg, A., . . . Carlstrom, M. (2018). Changes of arterial pressure following relief of obstruction in adults with hydronephrosis. Upsala Journal of Medical Sciences, 123(4), 216-224
Open this publication in new window or tab >>Changes of arterial pressure following relief of obstruction in adults with hydronephrosis
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2018 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 4, p. 216-224Article in journal (Refereed) Published
Abstract [en]

Background: As much as 20% of all cases of hypertension are associated with kidney malfunctions. We have previously demonstrated in animals and in pediatric patients that hydronephrosis causes hypertension, which was attenuated by surgical relief of the ureteropelvic junction (UPJ) obstruction. This retrospective cohort study aimed to investigate: (1) the proposed link between hydronephrosis, due to UPJ obstruction, and elevated arterial pressure in adults; and (2) if elevated blood pressure in patients with hydronephrosis might be another indication for surgery.

Materials and methods: Medical records of 212 patients undergoing surgical management of hydronephrosis, due to UPJ obstruction, between 2000 and 2016 were assessed. After excluding patients with confounding conditions and treatments, paired arterial pressures (i.e. before/after surgery) were compared in 49 patients (35 years old; 95% CI 29–39). Split renal function was evaluated by using mercaptoacetyltriglycine (MAG3) renography before surgical management of the hydronephrotic kidney.

Results: Systolic (−11 mmHg; 95% CI 6–15 mmHg), diastolic (−8 mmHg; 95% CI 4–11 mmHg), and mean arterial (-9 mmHg; 95% CI 6–12) pressures were significantly reduced after relief of the obstruction (p < 0.001). Split renal function of the hydronephrotic kidney was 39% (95% CI 37–41). No correlations were found between MAG3 and blood pressure level before surgery or between MAG3 and the reduction of blood pressure after surgical management of the UPJ obstruction.

Conclusions: In adults with hydronephrosis, blood pressure was reduced following relief of the obstruction. Our findings suggest that elevated arterial pressure should be taken into account as an indication to surgically correct hydronephrosis.

Keywords
Blood pressure, hydronephrosis, hypertension, kidney, renal function, ureteral obstruction
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-375862 (URN)10.1080/03009734.2018.1521890 (DOI)000455702800004 ()30293474 (PubMedID)
Funder
Swedish Research Council, 2016-01381Swedish Research Council, 65X-03522-43-3Swedish Heart Lung Foundation, 20140448; 20170124
Available from: 2019-02-01 Created: 2019-02-01 Last updated: 2019-02-01Bibliographically approved
Gao, X., Liu, Z. Z., Mohammed, H., Braun, D., Zhuge, Z., Liu, M., . . . Persson, A. E. (2018). Extravasal albumin concentration modulates contractile responses of renal afferent arterioles. Acta Physiologica, 222(2), Article ID e12925.
Open this publication in new window or tab >>Extravasal albumin concentration modulates contractile responses of renal afferent arterioles
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2018 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 222, no 2, article id e12925Article in journal (Refereed) Published
Abstract [en]

Aim: Afferent arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback, the afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates afferent arteriolar tone, a mechanism which may contribute to body fluid volume control.

Method: The effect of increased extravasal albumin concentration on the vascular reactivity was investigated in renal AA and interlobar arteries of mice, in rat renal AA and in pancreatic islet arterioles.

Results: Albumin (2 and 4% in the bath solution) significantly potentiated the contractile response of renal afferent arterioles induced by angiotensin II and adenosine, as well as their combination, compared to the control situation (0.1% albumin). Albumin did not influence the contractility of larger renal vessels or pancreatic islet arterioles. Mimicking the increase in the osmolality induced by 4% albumin by applying mannitol to the bath solution also increased the response of renal arterioles to Ang II. However, the effect was smaller compared to that of albumin. The nitric oxide bioavailability, measured by DAF-FM fluorescence, was reduced in afferent arterioles exposed to 4% albumin.

Conclusion: The protein-induced modulation of AA tone is mediated by the increased osmolality as well as by NO scavenging. The results suggest a possible contribution of these mechanisms to the control of extracellular fluid volume via adjustment of renal blood flow and glomerular filtration rate.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
adenosine, angiotensin II, glomerular filtration, nitric oxide, protein, renal autoregulation
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-343780 (URN)10.1111/apha.12925 (DOI)000423367700009 ()
Available from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-03-07Bibliographically approved
Yang, T., Zhang, X.-M., Tarnawski, L., Peleli, M., Zhuge, Z., Terrando, N., . . . Carlström, M. (2017). Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress. Redox Biology, 13, 320-330
Open this publication in new window or tab >>Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress
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2017 (English)In: Redox Biology, ISSN 0090-7324, E-ISSN 2213-2317, Vol. 13, p. 320-330Article in journal (Refereed) Published
Abstract [en]

Ischemia-reperfusion (IR) injury involves complex pathological processes in which reduction of nitric oxide (NO) bioavailability is suggested as a key factor. Inorganic nitrate can form NO in vivo via NO synthase-independent pathways and may thus provide beneficial effects during IR. Herein we evaluated the effects of dietary nitrate supplementation in a renal IR model. Male mice (C57BL/6J) were fed nitrate-supplemented chow (1.0 mmol/kg/day) or standard chow for two weeks prior to 30 min ischemia and during the reperfusion period. Unilateral renal IR caused profound tubular and glomerular damage in the ischemic kidney. Renal function, assessed by plasma creatinine levels, glomerular filtration rate and renal plasma flow, was also impaired after IR. All these pathologies were significantly improved by nitrate. Mechanistically, nitrate treatment reduced renal superoxide generation, pro-inflammatory cytokines (IL-1 beta, IL-6 and IL-12 p70) and macrophage infiltration in the kidney. Moreover, nitrate reduced mRNA expression of pro-inflammatory cytokines and chemo attractors, while increasing anti-inflammatory cytokines in the injured kidney. In another cohort of mice, two weeks of nitrate supplementation lowered superoxide generation and IL-6 expression in bone marrow-derived macrophages. Our study demonstrates protective effect of dietary nitrate in renal IR injury that may be mediated via modulation of oxidative stress and inflammatory responses. These novel findings suggest that nitrate supplementation deserve further exploration as a potential treatment in patients at high risk of renal IR injury.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Acute kidney injury, Inflammation, Inorganic nitrate, NADPH oxidase, Nitric oxide, Oxidative stress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-335128 (URN)10.1016/j.redox.2017.06.002 (DOI)000410470000025 ()28623824 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20140448Swedish Research Council, 2016-01381The Karolinska Institutet's Research Foundation, 2415/2012-225, 2-3707/2013
Available from: 2017-12-04 Created: 2017-12-04 Last updated: 2017-12-04Bibliographically approved
Peleli, M., Flacker, P., Zhuge, Z., Gomez, C., Wheelock, C. E., Persson, E. & Carlstrom, M. (2017). Renal denervation attenuates hypertension and renal dysfunction in a model of cardiovascular and renal disease, which is associated with reduced NADPH and xanthine oxidase activity. Redox Biology, 13, 522-527
Open this publication in new window or tab >>Renal denervation attenuates hypertension and renal dysfunction in a model of cardiovascular and renal disease, which is associated with reduced NADPH and xanthine oxidase activity
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2017 (English)In: Redox Biology, ISSN 0090-7324, E-ISSN 2213-2317, Vol. 13, p. 522-527Article in journal (Refereed) Published
Abstract [en]

Oxidative stress is considered a central pathophysiological event in cardiovascular disease, including hypertension. Early age reduction in renal mass is associated with hypertension and oxidative stress in later life, which is aggravated by increased salt intake. The aim of the present study was to examine if renal sympathetic denervation can exert blood pressure lowering effects in uninephrectomized (UNX) rats (3-week old) fed with high salt (HS, 4%; w/w) diet for 4 weeks. Moreover, we investigated if renal denervation is associated with changes in NADPH and xanthine oxidase-derived reactive oxygen species. Rats with UNX + HS had reduced renal function, elevated systolic and diastolic arterial pressures, which was accompanied by increased heart weight, and cardiac superoxide production compared to sham operated Controls. UNX + HS was also associated with higher expression and activity of NADPH and xanthine oxidase in the kidney. Renal denervation in rats with UNX + HS attenuated the development of hypertension and cardiac hypertrophy, but also improved glomerular filtration rate and reduced proteinuria. Mechanistically, renal de nervation was associated with lower expression and activity of both NADPH oxidase and xanthine oxidase in the kidney, but also reduced superoxide production in the heart. In conclusion, our study shows for the first time that renal denervation has anti-hypertensive, cardio- and reno-protective effects in the UNX + HS model, which can be associated with decreased NADPH oxidase- and xanthine oxidase-derived reactive oxygen species (i.e., superoxide and hydrogen peroxide) in the kidney.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Renal denervation, Xanthine oxidase, NADPH oxidase, Hypertension, Renal dysfunction, Cardiovascular disease
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-335129 (URN)10.1016/j.redox.2017.06.013 (DOI)000410470000047 ()28734244 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20140448Swedish Research Council, 2016-01381The Karolinska Institutet's Research Foundation, 2415/2012-225, 2-3707/2013
Available from: 2017-12-04 Created: 2017-12-04 Last updated: 2018-01-13Bibliographically approved
Turner, A. J., Brown, R. D., Brandon, A. E., Persson, E. & Gibson, K. J. (2017). Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes. American Journal of Physiology - Renal Physiology, 313(4), F864-F873
Open this publication in new window or tab >>Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes
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2017 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 313, no 4, p. F864-F873Article in journal (Refereed) Published
Abstract [en]

Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26-28 days gestation. No differences were observed in mean arterial pressure, glomcrular.filtration rate. or electrolyte excretion rates between the.Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex treatedfetuses was significantly lower (12.9 +/- 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 +/- 1.0 til/min). This resetting of TOE sensitivity persisted after birth (P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TOE sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TOE response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2017
Keywords
tubuloglomerular feedback, fetal programming, dexamethasone
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-338533 (URN)10.1152/ajprenal.00538.2016 (DOI)000412361700007 ()28679594 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2018-01-10 Created: 2018-01-10 Last updated: 2018-01-10Bibliographically approved
Peleli, M., Zollbrecht, C., Montenegro, M. F., Hezel, M., Zhong, J., Persson, E. G., . . . Carlström, M. (2016). Enhanced XOR activity in eNOS-deficient mice Effects on the nitrate-nitrite-NO pathway and ROS homeostasis. Free Radical Biology & Medicine, 99, 472-484
Open this publication in new window or tab >>Enhanced XOR activity in eNOS-deficient mice Effects on the nitrate-nitrite-NO pathway and ROS homeostasis
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2016 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 99, p. 472-484Article in journal (Refereed) Published
Abstract [en]

Xanthine oxidoreductase (XOR) is generally known as the final enzyme in purine metabolism and as a source of reactive oxygen species (ROS). In addition, this enzyme has been suggested to mediate nitric oxide (NO) formation via reduction of inorganic nitrate and nitrite. This NO synthase (NOS)-independent pathway for NO generation is of particular importance during certain conditions when NO bioavailability is diminished due to reduced activity of endothelial NOS (eNOS) or increased oxidative stress, including aging and cardiovascular disease. The exact interplay between NOS- and XOR-derived NO generation is not fully elucidated yet. The aim of the present study was to investigate if eNOS deficiency is associated with changes in XOR expression and activity and the possible impact on nitrite, NO and ROS homeostasis. Plasma levels of nitrate and nitrite were similar between eNOS deficient (eNOS(-/-)) and wildtype (wt) mice. XOR activity was upregulated in eNOS(-/-) compared with wt, but not in nNOS(-/-), iNOS(-/-) or wt mice treated with the non-selective NOS inhibitor L-NAME. Following an acute dose of nitrate, plasma nitrite increased more in eNOS(-/-) compared with wt, and this augmented response was abolished by the selective XOR inhibitor febuxostat. Livers from eNOS(-/-) displayed higher nitrite reducing capacity compared with wt, and this effect was attenuated by febuxostat. Dietary supplementation with nitrate increased XOR expression and activity, but concomitantly reduced superoxide generation. The latter effect was also seen in vitro after nitrite administration. Treatment with febuxostat elevated blood pressure in eNOS(-/-), but not in wt mice. A high dose of dietary nitrate reduced blood pressure in na ve eNOS(-/-) mice, and again this effect was abolished by febuxostat. In conclusion, eNOS deficiency is associated with an upregulation of XOR facilitating the nitrate-nitrite-NO pathway and decreasing the generation of ROS. This interplay between XOR and eNOS is proposed to play a significant role in NO homeostasis and blood pressure regulation.

Keywords
Nitrate, Nitrite, Nitric oxide, Xanthine oxidase, Xanthine oxidoreductase, Febuxostat, Hypertension, Endothelial nitric oxide synthase, Oxidative stress, Reactive oxygen species, Superoxide, Uric acid
National Category
Endocrinology and Diabetes Cell Biology
Identifiers
urn:nbn:se:uu:diva-310778 (URN)10.1016/j.freeradbiomed.2016.09.004 (DOI)000387995400044 ()27609225 (PubMedID)
Funder
Swedish Research Council, 521-2011-2639Swedish Heart Lung Foundation, 20110589 20140448Knut and Alice Wallenberg Foundation, KAW 2015.0063Stockholm County Council
Available from: 2016-12-19 Created: 2016-12-19 Last updated: 2017-11-29Bibliographically approved
Porpino, S. K. P., Zollbrecht, C., Peleli, M., Montenegro, M. F., Brandao, M. C. R., Athayde-Filho, P. F., . . . Carlstrom, M. (2016). Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II-mediated hypertension. British Journal of Pharmacology, 173(14), 2290-2302
Open this publication in new window or tab >>Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II-mediated hypertension
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2016 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 173, no 14, p. 2290-2302Article in journal (Refereed) Published
Abstract [en]

Background and PurposeNO deficiency and oxidative stress are crucially involved in the development or progression of cardiovascular disease, including hypertension and stroke. We have previously demonstrated that acute treatment with the newly discovered organic nitrate, 2-nitrate-1,3-dibuthoxypropan (NDBP), is associated with NO-like effects in the vasculature. This study aimed to further characterize the mechanism(s) and to elucidate the therapeutic potential in a model of hypertension and oxidative stress. Experimental ApproachA combination of ex vivo, in vitro and in vivo approaches was used to assess the effects of NDBP on vascular reactivity, NO release, NADPH oxidase activity and in a model of hypertension. Key ResultsEx vivo vascular studies demonstrated NDBP-mediated vasorelaxation in mesenteric resistance arteries, which was devoid of tolerance. In vitro studies using liver and kidney homogenates revealed dose-dependent and sustained NO generation by NDBP, which was attenuated by the xanthine oxidase inhibitor febuxostat. In addition, NDBP reduced NADPH oxidase activity in the liver and prevented angiotensin II-induced activation of NADPH oxidase in the kidney. In vivo studies showed that NDBP halted the progression of hypertension in mice with chronic angiotensin II infusion. This was associated with attenuated cardiac hypertrophy, and reduced NADPH oxidase-derived oxidative stress and fibrosis in the kidney and heart. Conclusion and ImplicationsThe novel organic nitrate NDBP halts the progression of angiotensin II-mediated hypertension. Mechanistically, our findings suggest that NDBP treatment is associated with sustained NO release and attenuated activity of NADPH oxidase, which to some extent requires functional xanthine oxidase.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-300542 (URN)10.1111/bph.13511 (DOI)000379675900010 ()27160064 (PubMedID)
Funder
Swedish Research Council, 521-2011-2639Swedish Heart Lung Foundation, 20140448Stockholm County CouncilThe Karolinska Institutet's Research Foundation
Available from: 2016-08-10 Created: 2016-08-09 Last updated: 2018-01-10Bibliographically approved
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