Endothelial-derived nitric oxide and angiotensinogen: blood pressure and metabolism during mouse pregnancy

2001 ◽  
Vol 280 (1) ◽  
pp. R174-R182 ◽  
Author(s):  
Lukas A. Hefler ◽  
Clemens B. Tempfer ◽  
Rene M. Moreno ◽  
William E. O'Brien ◽  
Anthony R. Gregg
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Urine Analysis ◽  
Renin Angiotensin System ◽  
Mutant Mice ◽  
Enos Gene ◽  
Metabolic Characteristics ◽  
Mutant Strains ◽  
Blood Pressures ◽  
Regulation Of Blood Pressure

The regulation of blood pressure during pregnancy involves several biological pathways. Candidate genes implicated in hypertensive diseases during pregnancy include those of the renin-angiotensin system and nitric oxide synthase (NOS). We evaluated blood pressure and metabolic characteristics during pregnancy in mutant mice. These included mice with a null mutation in the endothelial NOS (eNOS) gene ( Nos3−/− ), four copies of the angiotensinogen gene ( Agt2/2 ), and mutations in both genes [four copies of Agt and heterozygous deficient for eNOS (Agt2/2Nos3+/− ), four copies of Agt and homozygous deficient for eNOS ( Agt2/2Nos3−/− )]. Blood pressure measurements of nulliparous females from mutant strains were compared with two common laboratory strains C57Bl6/J and SV129 throughout their first pregnancy. Serum and urine analysis for the evaluation of renal and liver physiology were measured in the prepregnant state and during the third trimester of pregnancy. Throughout pregnancy blood pressures in all mutant strains were higher compared with controls. Agt2/2Nos3−/− showed the highest blood pressures and C57Bl6/J the lowest. Control mice, but not mutant mice, showed a second trimester decline in blood pressure. No immediate differences were noted regarding behavioral characteristics, renal or liver function parameters. Mice deficient for eNOS, mice with overexpression of Agt, and mice with mutations in both genes demonstrated higher blood pressure throughout pregnancy. There was no evidence of renal dysfunction, liver dysfunction, or hemolysis among any of the strains studied. We conclude that Nos3 and Agt are important genes in the regulation of blood pressure during pregnancy.

Human eNOS gene delivery attenuates cold-induced elevation of blood pressure in rats

2005 ◽  
Vol 289 (3) ◽  
pp. H1161-H1168 ◽  
Author(s):  
Xiuqing Wang ◽  
Robert Cade ◽  
Zhongjie Sun
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Nervous System ◽  
Gene Transfer ◽  
Renin Angiotensin System ◽  
Treated Group ◽  
Enos Gene ◽  
No Production ◽  
Angiotensin System ◽  
Sympathetic Nervous

We previously showed that chronic cold exposure inhibits endothelial nitric oxide synthase (eNOS) expression and decreases nitric oxide (NO) production. The aim of the present study was to evaluate the possible role of the NO system in the development of cold-induced hypertension (CIH) by testing the hypothesis that adenoviral delivery of human eNOS gene increases NO production and attenuates CIH in rats. The effect of in vivo delivery of adenovirus carrying human eNOS full-length cDNA (rAdv.heNOS) on CIH was tested using four groups of Sprague-Dawley rats (6 rats/group). Blood pressure (BP) did not differ among the four groups during the control period at room temperature (24°C). Two groups of rats received intravenous injection of rAdv.heNOS (1 × 109plaque-forming units/rat), and the other two groups received the same dose of rAdv.LacZ to serve as controls. After gene delivery, one rAdv.heNOS-treated group and one rAdv.LacZ-treated group were exposed to cold (6°C) while the remaining groups were kept at 24°C. We found that the BP of the rAdv.LacZ group increased significantly within 1 wk of exposure to cold and reached a peak level at week 5 (152.2 ± 6.4 mmHg). In contrast, BP (118.7 ± 8.4 mmHg) of the cold-exposed rAdv.heNOS group did not increase until 5 wk after exposure to cold. The rAdv.heNOS increased plasma and urine levels of NO significantly in cold-exposed rats, which indicates that eNOS gene transfer increased NO production. Notably, rAdv.heNOS decreased plasma levels of norepinephrine and plasma renin activity in cold-exposed rats, which suggests that eNOS gene transfer may decrease the activities of the sympathetic nervous system and the renin-angiotensin system. Immunohistochemical analysis showed that the transferred human eNOS was expressed in both endothelium and adventitia of mesenteric arteries. We conclude that 1) eNOS gene transfer attenuates CIH by increasing NO production and inhibiting the sympathetic nervous system and the renin-angiotensin system; and 2) the NO system appears to mediate this nongenetic, nonpharmacological, nonsurgical model of hypertension.

scholarly journals Blood pressure and renal blow flow responses in heme oxygenase-2 knockout mice

2009 ◽  
Vol 297 (6) ◽  
pp. R1822-R1828 ◽  
Author(s):  
David E. Stec ◽  
Trinity Vera ◽  
Megan V. Storm ◽  
Gerald R. McLemore ◽  
Michael J. Ryan
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Heme Oxygenase ◽  
Acute Administration ◽  
Ang Ii ◽  
Wild Type ◽  
Renal Circulation ◽  
Kidney Weight ◽  
Blood Pressures ◽  
Regulation Of Blood Pressure

Heme oxygenase (HO) is the enzyme responsible for the breakdown of heme-generating carbon monoxide (CO) and biliverdin in this process. HO-2 is the constitutively expressed isoform in most tissues, such as the kidney and vasculature. CO generated by HO is believed to be an important vasodilator in the renal circulation along with another gas, nitric oxide (NO). To determine the importance of HO-2 in the regulation of blood pressure and renal blood flow (RBF), we treated HO-2 knockout (KO) mice chronically with either ANG II or NG-nitroarginine methyl ester (l-NAME). Basal blood pressures were not different between wild-type (WT), heterozygous (HET), or KO mice and averaged 113 ± 3 vs. 115 ± 2 vs. 116 ± 2 mmHg. Similar increases in blood pressure to chronic ANG II as well as l-NAME treatment were observed in all groups with blood pressures increasing an average of 30 mmHg in response to ANG II and 15 mmHg in response to l-NAME. Basal RBFs were not different between the groups averaging 6.0 ± 0.5 ( n = 6) vs. 4.8 ± 0.6 ( n = 10) vs. 5.8 ± 0.7 ( n = 6) ml·min−1·g−1 kidney weight in WT, HET, and KO mice. HO-2 KO and HET mice exhibited an attenuated decrease in RBF in response to acute administration of ANG II, while no differences were observed with l-NAME. Our data indicate that blood pressure and RBF responses to increased ANG II or inhibition of nitric oxide are not significantly enhanced in HO-2 KO mice.

Role of nitric oxide and prostaglandins in the regulation of blood pressure in conscious rats

1995 ◽  
Vol 73 (6) ◽  
pp. 693-698 ◽  
Author(s):  
Andrés C. Inglés ◽  
Francisco J. Ruiz ◽  
Miguel G. Salom ◽  
Tomás Quesada ◽  
Luis F. Carbonell
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Methyl Ester ◽  
Pressor Response ◽  
Specific Inhibitor ◽  
Renin Angiotensin System ◽  
Conscious Rats ◽  
Endogenous Nitric Oxide ◽  
Regulation Of Blood Pressure

The present study was designed to investigate the possible role of endothelium-derived vasodilators, nitric oxide and prostaglandins, in the regulation of blood pressure during the presence and absence of the major pressor systems. Conscious rats were infused with a cocktail of inhibitors of the sympathetic nervous system, renin–angiotensin system, and V1 vascular receptor to vasopressin (achieved with hexamethonium, captopril, phentolamine, propranolol, and the V1 vasopressin (AVP) antagonist des-(CH2)5Tyr(Me)-AVP). The cocktail of vasoconstrictor inhibitors induced a marked fall of mean arterial pressure (MAP) from 109 ± 2 to 52 ± 2 mmHg (1 mmHg = 133.3 Pa) (n = 24). In animals with blockade, the specific inhibitor of nitric oxide synthesis, NG-nitro-L-arginine methyl ester (L-NAME), induced a significant increase of MAP from 51 ± 1 to 84 ± 2 mmHg (n = 6). In the presence of indomethacin, a cyclooxygenase inhibitor, the pressor response to L-NAME was from 52 ± 2 to 126 ± 4 mmHg (n = 6). Neither indomethacin (n = 6) nor vehicle (n = 6) alone altered MAP. In intact animals without blockade, L-NAME caused a similar increase of MAP when it was injected alone (from 107 ± 3 to 144 ± 4 mmHg, n = 7) or with indomethacin (from 113 ± 3 to 144 ± 3, n = 6). Indomethacin alone (n = 8) did not change MAP. In conclusion, in the absence of the major pressor systems, the pressor effect of the inhibition of the production of endogenous nitric oxide and vasodilator prostanoid synthesis appears to be synergistic. These results suggest that these two endogenous vasodilators are involved in the maintenance of blood pressure.Key words: nitric oxide, NG-nitro-L-arginine methyl ester, prostaglandins, blood pressure.

scholarly journals Nitric oxide synthase-mediated blood pressure regulation in obese melanocortin-4 receptor-deficient pregnant rats

2016 ◽  
Vol 311 (5) ◽  
pp. R851-R857 ◽  
Author(s):  
Frank T. Spradley ◽  
Jennifer M. Sasser ◽  
Jacqueline B. Musall ◽  
Jennifer C. Sullivan ◽  
Joey P. Granger
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Mesenteric Arteries ◽  
Elevated Blood Pressure ◽  
Pressure Regulation ◽  
Elevated Blood ◽  
Pregnant Rats ◽  
Melanocortin 4 Receptor ◽  
Regulation Of Blood Pressure

Although obesity increases the risk for hypertension in pregnancy, the mechanisms responsible are unknown. Increased nitric oxide (NO) production results in vasodilation and reduced blood pressure during normal pregnancy in lean rats; however, the role of NO is less clear during obese pregnancies. We examined the impact of obesity on NO synthase (NOS)-mediated regulation of blood pressure during pregnancy by testing the hypothesis that NOS activity, expression, and regulation of vascular tone and blood pressure are reduced in obese pregnant rats. At gestational day 19, melanocortin-4 receptor (MC4R)-deficient obese rats (MC4R) had greater body weight and fat mass with elevated blood pressure and circulating sFlt-1 levels compared with MC4R pregnant rats. MC4R pregnant rats also had less circulating cGMP levels and reduced total NOS enzymatic activity and expression in mesenteric arteries. Despite decreased biochemical measures of NO/NOS in MC4R rats, NOS inhibition enhanced vasoconstriction only in mesenteric arteries from MC4R rats, suggesting greater NOS-mediated tone. To examine the role of NOS on blood pressure regulation in obese pregnant rats, MC4R and MC4R pregnant rats were administered the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 100 mg/l) from gestational day 14 to 19 in drinking water. The degree by which l-NAME raised blood pressure was similar between obese and lean pregnant rats. Although MC4R obese pregnant rats had elevated blood pressure associated with reduced total NOS activity and expression, they had enhanced NOS-mediated attenuation of vasoconstriction, with no evidence of alterations in NOS-mediated regulation of blood pressure.

scholarly journals Mitochondrial function and nitric oxide metabolism are modified by enalapril treatment in rat kidney

2007 ◽  
Vol 292 (4) ◽  
pp. R1494-R1501 ◽  
Author(s):  
Barbara Piotrkowski ◽  
Cesar G. Fraga ◽  
Elena M. V. de Cavanagh
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Mitochondrial Function ◽  
Uncoupling Protein ◽  
Rat Kidney ◽  
Blood Pressure Reduction ◽  
Renin Angiotensin System ◽  
Renal Protection ◽  
Kidney Mitochondria ◽  
Ras Inhibition

The renal and cardiac benefits of renin-angiotensin system (RAS) inhibition in hypertension exceed those attributable to blood pressure reduction, and seem to involve mitochondrial function changes. To investigate whether mitochondrial changes associated with RAS inhibition are related to changes in nitric oxide (NO) metabolism, four groups of male Wistar rats were treated during 2 wk with a RAS inhibitor, enalapril (10 mg·kg−1·day−1; Enal), or a NO synthase (NOS) inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME) (1 mg·kg−1·day−1), or both (Enal+l-NAME), or were untreated (control). Blood pressure and body weight were lower in Enal than in control. Electron transfer through complexes I to III and cytochrome oxidase activity were significantly lower, and uncoupling protein-2 content was significantly higher in kidney mitochondria isolated from Enal than in those from control. All of these changes were prevented by l-NAME cotreatment and were accompanied by a higher production/bioavailability of kidney NO. l-NAME abolished mitochondrial NOS activity but failed to inhibit extra-mitochondrial kidney NOS, underscoring the relevance of mitochondrial NO in those effects of enalapril that were suppressed by l-NAME cotreatment. In Enal, kidney mitochondria H2O2 production rate and MnSOD activity were significantly lower than in control, and these effects were not prevented by l-NAME cotreatment. These findings may clarify the role of NO in the interactions between RAS and mitochondrial metabolism and can help to unravel the mechanisms involved in renal protection by RAS inhibitors.

Blood Cell Versus Vascular Endothelial Cell Contributions to Nitrite Homeostasis and Blood Pressure Regulation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4601-4601
Author(s):  
Katherine C Wood ◽  
Virginia B Liu ◽  
Audrey Noguchi ◽  
Xunde Wang ◽  
Nalini Raghavachari ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Cell ◽  
Whole Blood ◽  
Blood Cells ◽  
Pressure Regulation ◽  
Chimeric Mice ◽  
Blood Pressures ◽  
Plasma Nitrite ◽  
Positive Controls

Abstract Mice genetically deficient in constitutive nitric oxide synthase (eNOS) are hypertensive compared to normal C57Bl6 (wild type) mice, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. The objective of this study was to use molecular methodologies to determine the contribution of eNOS in circulating blood cells to the intravascular pool of nitrite, a metabolite and storage form of nitric oxide (NO•) with powerful vasorelaxant activity, and to the regulation of blood pressure under physiological conditions. We used bone marrow transplant to create chimeric mice genetically deficient in eNOS in either circulating blood cells (−/+) or vascular endothelium (+/−), confirmed by flow cytometry, western blot, RT-PCR and immunohistochemistry. Nitrite concentrations in whole blood and plasma of chimeras were quantified using ozone-based reductive chemiluminescence. Mean arterial and diastolic blood pressures of chimeras were assessed in the absence/presence of NOS stimulation with oral L-Arginine or NOS inhibition with oral L-Name. A highly significant inverse correlation between plasma nitrite concentrations and blood pressures was noted across all groups of chimeric mice. Importantly, in agreement with higher blood pressures in −/+ chimeras compared to eNOS positive controls (+/+ chimeras globally competent for eNOS), significantly reduced whole blood and plasma nitrite concentrations were also measured. Blood pressure responses to NOS inhibition or stimulation were intact in all chimera groups except eNOS negative controls (−/− chimeras globally deficient for eNOS) and, importantly, blunted in −/+ chimeras compared to eNOS positive controls. These findings indicate a functional blood cell eNOS that is a major contributor to circulating nitrite concentrations and plays a critical role in vascular homeostasis.

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