Effects of chronic NO synthase inhibition in rats on renin-angiotensin system and sympathetic nervous system

Zanchi, Anne; Schaad, Nicolas; Osterheld, Maria‐Chiara; Grouzmann, Eric; Nussberger, Jürg; Brunner, Hans R.; Waeber, Bernard

doi:10.1152/ajpheart.1995.268.6.h2267

Cited by 63 publications

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“…Chronic administration of L-NAME in drinking water (0.4 g/l) during 6 weeks decreases NO synthase activity in the rat brain to less than 16% [17]. It has however not yet been demonstrated whether NO synthase remains inhibited in vitro when the arteries are obtained from rats chronically treated with an NO synthase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Vascular acetylcholine response during chronic NO synthase inhibition: in vivo versus in vitro

Zanchi

Aubert

Brunner

et al. 1995

Cardiovascular Research

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Objective: The aim of this study was to compare the response to NO-mediated vasodilators in vivo and in vitro during chronic NO synthase inhibition. Methds: NG-Nitro-L-arginine-methyl ester (L-NAME, 0.4 g/l) or vehicle was administered in the drinking water for 6 weeks to male Wistar rats weighing 220-240 g. The effect of acetylcholine and sodium nitroprusside was examined in vivo, on systemic blood pressure and heart rate and in vitro, on the precontracted isolated mesenteric artery. The in vivo response to both vasodilators was examined in awake rats monitored by an indwelling catheter in the femoral artery. Isolated segments of the third-generation mesenteric artery were examined in vitro with a Mulvany dual myograph after precontraction with noradrenaline. Resultsr In isolated mesenteric arteries obtained from rats chronically treated with L-NAME, the initial relaxant response to acetylcholine was significantly decmased whereas that to sodium nitroprusside was enhanced. A late acetylcholine-induced contractile response was present and abolished by indomethacin. In vivo, the hypotensive action of sodium nitroprusside was also enhanced in the L-NAME-treated rats. Acetylcholine reduced blood pressure in the L-NAME-treated hypertensive animals more than in normotensive controls, but less than in control rats infused intravenously with noradrenaline at a dose increasing their blood pressure to hypertensive levels. Conclusions: The NO-mediated vasodilation induced by acetylcholine is attenuated during chronic NO synthase inhibition, both in vivo and in vitro. The blunted hypotensive response to acetylcholine can be demonstrated only if blood pressure of control rats is acutely increased to hypertensive levels.

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Section: Discussionmentioning

confidence: 99%

Vascular acetylcholine response during chronic NO synthase inhibition: in vivo versus in vitro

Zanchi

Aubert

Brunner

et al. 1995

Cardiovascular Research

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“…10 Thus, in the peripheral circulation, Rho-kinase is apparently involved in the mechanisms of L-NAME-induced hypertension. There is evidence that L-NAME crosses the blood-brain barrier when administered orally 23 and the sympathetic nervous system is involved primarily in the maintenance, rather than initiation, of L-NAME-induced hypertension. 24,25 Furthermore, activation of the Rho/Rho-kinase pathway in the NTS plays an important role in the maintenance of the basal arterial blood pressure via the sympathetic nervous system.…”

Section: Discussionmentioning

confidence: 99%

Rho/Rho-Kinase Pathway in the Brainstem Contributes to Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition

et al. 2004

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Abstract-Central nervous system mechanisms are involved in hypertension caused by chronic inhibition of nitric oxide (NO) synthesis. Chronic inhibition of NO synthesis might also activate the Rho/Rho-kinase pathway in the vasculature.We recently demonstrated that activation of the Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) contributes to hypertensive mechanisms in spontaneously hypertensive rats. The aim of the present study was to determine whether activation of this pathway also contributes to neurogenic hypertensive mechanisms caused by chronic NO synthesis inhibition. The NO synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME) was administered to Wistar-Kyoto rats in their drinking water (1 mg/mL) for 2 weeks. Bilateral microinjection of Y-27632, a specific Rho-kinase inhibitor, into the NTS elicited decreases in arterial pressure, heart rate, and renal sympathetic nerve activity in control rats and L-NAME-treated rats. The magnitude of the decrease, however, was significantly greater in L-NAME-treated than in control rats. In another group of rats, the specific Rho-kinase inhibitor, Y-27632, was administered intracisternally for 2 weeks with a mini-osmotic pump from the beginning of treatment with L-NAME. Y-27632 co-treatment significantly attenuated the increase in arterial pressure. Furthermore, the expression level of membranous RhoA and phosphorylation of the target proteins of Rho-kinase, the ERM (ezrin, radixin, moesin) family members, was significantly greater in L-NAME-treated rats than in control rats. These results indicate that activation of the Rho/Rho-kinase pathway in the NTS contributes to neurogenic hypertension caused by chronic NO synthase inhibition. Key Words: nitric oxide Ⅲ blood pressure Ⅲ sympathetic nervous system Ⅲ hypertension Ⅲ brain I nhibition of nitric oxide (NO) synthesis produces hypertension in many species. 1,2 Although this hypertension was initially attributed to the inhibition of endothelial NO synthesis, numerous studies suggest that inhibition of neuronal NO also plays an important role in blood pressure regulation. [3][4][5][6][7] A previous study demonstrated that increased sympathetic nerve activity plays a role in hypertension caused by chronic NO synthesis inhibition, and activation of the renin-angiotensin system in the nucleus tractus solitarii (NTS) of the brainstem via angiotensin II type 1 receptors is involved. 8 Chronic inhibition of NO synthesis might activate the Rho/ Rho-kinase pathway in the cardiac tissues or vasculature. 9,10 The Rho/Rho-kinase pathway regulates the phosphorylation state of myosin light chains and contributes to smooth muscle contraction. 11 Y-27632, a specific Rho-kinase inhibitor, dramatically reduces blood pressure in rat models of hypertension. 12 In addition, Rho-kinase activity is augmented in hypertensive blood vessels 13 and inhibition of Rho-kinase induces preferential forearm vasodilatation in hypertensive patients, but not in normal subjects. 14 Thus, the Rho/Rhokinase pathway plays an important r...

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“…17,21 The reported effects of prolonged NO synthesis inhibition on PRA levels are contradictory. 13,16,19,21,22 One possible reason for this discrepancy is the different doses of NO synthesis inhibitors and different experimental protocols used. In this study, PRA decreased on the first day of L-NAME infusion and then increased, despite the fact that MAP remained elevated.…”

Section: Discussionmentioning

confidence: 99%

Role of Nitric Oxide and Prostaglandins in the Long-term Control of Renal Function

et al. 1998

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Abstract-Previous studies have reported evidence of an important interaction between nitric oxide (NO) and prostaglandins in the acute regulation of renal function. The objective of this study was to determine in conscious dogs whether the renal effects of the prolonged administration of a cyclooxygenase inhibitor are enhanced when NO synthesis is reduced. Meclofenamate infusion (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) during 4 consecutive days (nϭ8) elicited a continuous decrease (PϽ0.05) in renal blood flow and plasma renin activity and a transitory decrease in sodium excretion. N G -Nitro-Larginine methyl ester (L-NAME) infusion (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) during 6 days (nϭ8) produced a significant increase in arterial pressure and a transitory decrease (PϽ0.05) in both renal blood flow and plasma renin activity. The simultaneous inhibition of NO and prostaglandin synthesis (nϭ7) led to an increase in arterial pressure and a decrease in renal blood flow similar to those observed during the administration of either L-NAME or meclofenamate. In contrast, this simultaneous inhibition produced a decrease in glomerular filtration rate, which was not observed in the previous groups, and also induced an increase in renal vascular resistance and a decrease in sodium excretion greater (PϽ0.05) than those found during the inhibition of either NO or prostaglandins. Only a transitory decrease in plasma renin activity was found during meclofenamate infusion in this group. The results of this study present new evidence that the renal vasoconstrictor and antinatriuretic effects induced by the prolonged infusion of a cyclooxygenase inhibitor are significantly enhanced when NO synthesis is reduced. These results suggest that renal function may be more sensitive to the prolonged administration of a cyclooxygenase inhibitor in situations where NO production is reduced. (Hypertension. 1998;32:33-38.) Key Words: vasoconstriction Ⅲ nitric oxide Ⅲ prostaglandins Ⅲ sodium Ⅲ plasma renin activity T he role of NO and PG in the acute and long-term regulation of arterial pressure and renal function has been examined in many studies (see References 1 through 4 for review). It has been reported that acute and long-term NO synthesis inhibition induces a significant elevation in arterial pressure and RVR and a decrease in the renal excretory ability.1-3 The results obtained during the acute administration of a cyclooxygenase inhibitor are contradictory, but it is generally accepted that it can induce small changes in RVR and sodium excretion.2,4 The effects of the prolonged PG synthesis inhibition on renal function have been evaluated, but changes in RBF during the first days of cyclooxygenase inhibition have been only partly examined. 2,4Results obtained in previous studies performed in anesthetized dogs suggest that an important interaction exists between NO and PG in the acute regulation of renal hemodynamic and excretory function. 5,6 It was found that the renal effects induced by acute intrarenal L-NAME administration are significantly potentiated when PG s...

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Effects of chronic NO synthase inhibition in rats on renin-angiotensin system and sympathetic nervous system

Cited by 63 publications

References 0 publications

Vascular acetylcholine response during chronic NO synthase inhibition: in vivo versus in vitro

Vascular acetylcholine response during chronic NO synthase inhibition: in vivo versus in vitro

Rho/Rho-Kinase Pathway in the Brainstem Contributes to Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition

Role of Nitric Oxide and Prostaglandins in the Long-term Control of Renal Function

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