Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension (original) (raw)
Related papers
Effect of Reduction of Nitric Oxide on Plasma and Kidney Tissue Angiotensin II Levels
Amer J Hypertens, 1997
Nitric oxide synthase (NOS) blockade increases blood pressure (BP) and modifies glomerular and tubular function. Angiotensin II (AII) blockade restores glomerular and tubular function but does not lower BP. We measured plasma renin activity (PRA), plasma (AIIp), and kidney tissue (AIIk) AII with radioimmunoassay to investigate the dissociation between renal and systemic effects of NOS blockade. Two period clearance studies followed by plasma and renal tissue harvesting were performed in seven groups of rats. Groups 1 and 1A served as controls. Groups 2 and 2A received NaCl-NaHCO 3 during the first period and N Gmonomethyl-L-arginine (L-NMMA, 0.5 mg/kg/min) during the second period. Group 3 was similar to group 2 but renal perfusion pressure (RPP) was maintained constant by using an aortic snare. Groups 4 and 4A received N G -nitro-L-arginine-methyl ester (L-NAME, 5 mg/100 mL of drinking water) for 2 weeks. NOS blockers decreased AIIp (group 1, 74 ؎ 7 pg/mL; group 2, 22 ؎ 1 pg/mL; group 3, 26 ؎ 1 pg/ mL; group 4, 19 ؎ 3 pg/mL). The decrease in AIIp was a direct effect of L-NMMA independent of changes in perfusion pressure, as AIIp was similar in group 3 (normal RPP) and groups 2 and 4 (increased RPP). Measurements of PRA and AIIp demonstrated a similar reduction in PRA and AIIp in rats treated with NOS blocker. Although NOS blockers decreased AIIp, acute or chronic administration of NOS blockers did not modify AIIk (group 1, 1,192 ؎ 51; group 2, 1,354 ؎ 85; group 3, 1,348 ؎ 180; group 4, 1,276 ؎ 172 pg/kidney). Our findings demonstrate that NO blockers produce a dissociation between plasma and kidney AII levels. This dissociation can explain the beneficial effects of AII blockers on renal function and their lack of antihypertensive effects in anesthetized rats treated with NOS blockers. Am J
Some Aspects of Role of Nitric Oxide in the Mechanisms of Hypertension (Experimental Study)
Cardiology Research
Background: Modulation of endothelial function is a therapeutic option to reduce some of the significant complications of hypertension. However, the relationship between endothelial dysfunction reduced nitric oxide (NO) production, and the development of hypertension is not fully understood. To establish a potential pathogenetic link between impaired NO synthesis and hypertension, we investigated the results of competitive interaction of the substrate of NO synthase, Larginine, and its analog, an non-selective inhibitor of NO synthase, N-nitro-methyl ether-L-arginine (L-NAME), in experimental rats. Methods: Arterial hypertension was induced in male Wistar rats by intraperitoneal administration of L-NAME (Sigma-Aldrich) for 4-7 weeks. During the last 3 weeks, to a separate group of animals simultaneously with L-NAME, L-arginine (Sigma-Aldrich) was administered. In animals monitored for systolic and diastolic pressure, the level of NO in blood samples was determined spectrophotometrically using a Griess reagent. Results: Administration of L-NAME for 4-7 weeks induced an irreversible decrease of NO content in blood, a reversible increase of systolic pressure (SP) and diastolic pressure (DP), and an irreversible increase in pulse pressure (PP). In rats against the background of 7 weeks of intraperitoneal administration of L-NAME, during the last 3 weeks, they were injected with L-arginine, the SP and DP indices returned to their initial values, PP decreased and the NO content in arterial blood increased. Conclusions: The results of the study indicate the presence of residual endothelial dysfunction (characterized by insufficient NO) after the correction of hypertension. Therefore, in developing the new therapeutic approaches for the treatment of hypertension, it is necessary to include drugs that, in addition to correcting blood pressure, will support normalization, and potentiation of endothelial function and endogenous NO synthesis.
Renoprotective effects of nitric oxide in angiotensin II-induced hypertension in the rat
The American journal of physiology, 1998
Experiments were performed in anesthetized male Sprague-Dawley rats to determine whether increased nitric oxide (NO) activity during the development of hypertension exerts a protective effect on renal cortical blood flow (CBF) and medullary blood flow (MBF). The effects of acute NO synthase inhibition on renal function and on CBF and MBF, measured by laser-Doppler flow probes, were evaluated in control and ANG II-infused hypertensive rats, prepared by the infusion of ANG II at a rate of 65 ng/min via osmotic minipumps implanted subcutaneously for 13 days. In normotensive rats (n = 8), intravenous infusion of N omega-nitro-L-arginine (NLA; 20 micrograms.100 g-1.min-1) decreased CBF by 21 +/- 4% and MBF by 49 +/- 8% and increased blood pressure from 118 +/- 1 to 140 +/- 2 mmHg. In ANG II-infused rats (n = 7), CBF and MBF decreased by 46 +/- 5% and 25 +/- 6%, respectively, during infusion of NLA. Arterial pressure increased from 160 +/- 5 to 197 +/- 7 mmHg, which was a greater absolute...
Cardiovascular Research, 1999
Since the effects of angiotensin II receptor antagonism on arterial function in nitric oxide (NO)-deficient hypertension are unknown, we investigated the influence of losartan therapy (20 mg kg-1 day-1) on the control of arterial tone in NG-nitro-L-arginine methyl ester (L-NAME; 20 mg kg-1 day-1)-induced hypertension. Forty Wistar rats were divided into four groups: control, losartan, L-NAME, and losartan + L-NAME. The responses of isolated mesenteric arterial rings were examined in standard organ chambers after 8 treatment weeks. Losartan therapy prevented the development of L-NAME-induced hypertension and the associated impairments of endothelium-independent relaxations to nitroprusside, isoprenaline, and cromakalim, vasodilators acting via the formation of NO, activation of beta-adrenoceptors and opening of K+ channels, respectively. In addition, endothelium-dependent relaxations of noradrenaline-precontracted rings to acetylcholine during NO synthase inhibition in vitro were decreased in L-NAME rats, and clearly improved by losartan therapy. The inhibition of cyclooxygenase by diclofenac improved the responses to acetylcholine more effectively in L-NAME than losartan + L-NAME rats, but the relaxations remained decreased in L-NAME rats when compared with losartan + L-NAME rats. When hyperpolarization of smooth muscle was prevented by precontractions induced by high concentration of KCl, the responses to acetylcholine during combined NO synthase and cyclooxygenase inhibition were similar and almost abolished in all groups. Furthermore, superoxide dismutase, a scavenger of superoxide anions, enhanced the acetylcholine-induced relaxations more effectively in L-NAME than losartan + L-NAME rats, although plasma antioxidant capacity was similar in all study groups. Chronic L-NAME-induced hypertension was associated with attenuated arterial relaxation via endothelium-dependent and -independent mechanisms, both of which were improved by the losartan treatment. The mechanisms whereby losartan enhanced arterial relaxation in this model of experimental hypertension may have included enhanced hyperpolarization and increased sensitivity to NO in smooth muscle, and decreased vascular production of superoxide and vasoconstrictor prostanoids.
Renal Medullary Nitric Oxide Deficit of Dahl S Rats Enhances Hypertensive Actions of Angiotensin II
2002
Studies were designed to examine the hypothesis that the renal medulla of Dahl salt-sensitive (Dahl S) rats has a reduced capacity to generate nitric oxide (NO), which diminishes the ability to buffer against the chronic hypertensive effects of small elevations of circulating angiotensin II (AngII). Nitric oxide synthase (NOS) activity in the outer medulla of Dahl S rats (argininecitrulline conversion assay) was significantly reduced. This decrease in NOS activity was associated with the down regulation of protein expression of NOS I, NOS II and NOS III isoforms in this region as determined by Western blot analysis. In anesthetized Dahl S rats, we observed that a low subpressor i.v. infusion of AngII (5 ng/kg/min) did not increase the concentration of NO in the renal medulla as measured by a microdialysis with oxyhemoglobin trapping technique. In contrast, AngII produced a 38 % increase in the concentration of NO (87+8 to 117+8 nmol/L) in the outer medulla of Brown Norway rats. The same i.v. dose of AngII reduced renal medullary blood flow as determined by laser-Doppler flowmetry in Dahl S, but not in BN rats. A 7-day i.v. AngII infusion at a dose of 3 ng/kg/min did not change mean arterial pressure (MAP) in the BN rats, but increased MAP in Dahl S rats from 120 + 2 to 138 + 2 mmHg (P<0.05). AngII failed to increase MAP after NO substrate was provided by infusion of L-arginine (300 g/kg/min) into the renal medulla of Dahl S rats. Intravenous infusion of Larginine at the same dose had no effect on the AngII-induced hypertension. These results indicate that an impaired NO counterregulatory system in the outer medulla of Dahl S rats makes them more susceptible to the hypertensive actions of small elevations of AngII.
Nitric oxide, angiotensin II, and hypertension
Seminars in Nephrology, 2004
Although initially adaptive, the changes that accompany hypertension, namely, cell growth, endothelial dysfunction, and extracellular matrix deposition, eventually can become maladaptive and lead to end-organ disease such as heart failure, coronary artery disease, and renal failure. A functional imbalance between angiotensin II (Ang II) and nitric oxide (NO) plays an important pathogenetic role in hypertensive end-organ injury. NO, an endogenous vasodilator, inhibitor of vascular smooth muscle and mesangial cell growth, and natriuretic agent, is synthesized in the endothelium by a constitutive NO synthase. NO antagonizes the effects of Ang II on vascular tone, cell growth, and renal sodium excretion, and also down-regulates the synthesis of angiotensin-converting enzyme (ACE) and Ang II type 1 receptors. On the other hand, Ang II decreases NO bioavailability by promoting oxidative stress. A better understanding of the pathophysiologic mechanisms involved in hypertensive end-organ damage may aid in identifying markers of cardiovascular susceptibility to injury and in developing therapeutic interventions. We propose that those antihypertensive agents that lower blood pressure and concomitantly restore the homeostatic balance of vasoactive agents such as Ang II and NO within the vessel wall would be more effective in preventing or arresting end-organ disease.
Receptors & channels, 2004
Losartan, an angiotensin II type-1 receptor (AT1) antagonist, was used to investigate whether it can offer protection against the sustained hypertension, cardiac hypertrophy, and renal damage induced by chronic inhibition of nitric oxide (NO) by Nomega-nitro-L-arginine methyl ester (L-NAME). We studied the involvement of both NO metabolism and oxidative stress in L-NAME-induced hypertension, and how AT1 receptor antagonism may interact. Male Wistar albino rats were subjected to NO synthesis inhibition by the use of L-NAME (60 mg/kg/day), and the effects of losartan (10 mg/kg/day) in drinking water for six weeks were observed. After six weeks, animals were subjected to the measurements for systolic, mean, and diastolic blood pressure (BPs, BPm, and BPd, respectively). Under light ether anesthesia blood was withdrawn for ACE activity, NOx and creatinine determinations. Heart and kidneys were weighed, and organ indices were calculated comparing to their body weights. These tissues were...
Regional Hemodynamics after Chronic Nitric Oxide Inhibition In Spontaneously Hypertensive Rats
American Journal of The Medical Sciences, 2000
Background: Inhibition of nitric o-ide (NO) synthase by l-arginine analogs is associated with elevation of blood pressure in rats. Because endothelium-dependent vasomotion in different vascular beds is not homogenous, the aim of this study was to characterize and compare regional hemodynamic responses in carotid, femoral, and renal vascular beds after chronic NO inhibition in spontaneously hypertensive rats. The possible role of circulating endothelin and renin angiotensin systems in mediating the effects of chronic NO inhibition was also studied.
Introduction: higher blood pressure and organ damage were always observed in chronic hypertension. Here, we have investigated in female uninephrectomized spontaneously hypertensive rats (UNX-SHRs) the role of NO on changes in blood pressure, renal function, thoracic aortic relaxations and structure. Materials and Methods: UNX-SHRs have been chronic treated with D-and L-arginine (D-and L-Arg; 1 mg kg-1 day-1 during 6 months in drinking water) alone or in the presence of low doses of Nw-nitro-Larginine methyl ester (L-NAME; 1 mg kg-1 day-1 the first month and 0.5 mg kg-1 day-1 during the next 5 months in drinking water). Mean blood pressure (MAP) was measured by the tail-cuff procedure. Plasma and urine levels of creatinine (Jaffé reaction), urinary proteins (Bradford method), as well as, urinary sodium and potassium (flame photometer) were determined for to evaluate renal function. Nitrite production in plasma was also measured by the Griess reaction. Segments of thoracic aortas were used to analyze vascular reactivity and morphology. Results: at the end of the study, the MAP was higher in UNX-SHRs treated with L-NAME+D-Arg and L-NAME+L-Arg than D-or L-arginine alone. There were no differences between groups on renal function. Vascular relaxation induced by acetylcholine (endothelium-depedent relaxation) was higher in animals treated by L-Arg vs. D-Arg, but was similar to L-NAME treated animals. In contract, vascular relaxation induced by sodium nitroprusside (endothelium-independent relaxation) was similar in all treated UNX-SHRs. Structural changes in thoracic aorta were linked to pressure load, as well as, NO production. Conclusion: we could suggest in UNX-SHRs treated during 6 months with low doses of NO related drugs that: a) renal dysfunction may be an independent process from vascular response and vascular reactivity; and b) functional and structural changes in thoracic aorta seems to be linked to both pressure load, and changes in NO production INTRODUCTION