Effects of chronic treatment with nitric oxide synthase inhibitors on regional haemodynamic responses to vasodilators in conscious Brattleboro rats

1 Vascular responses to acetylcholine and sodium nitroprusside in vivo and in vitro, in the isolated perfused kidney and in rings of rat thoracic aorta, were measured in rats treated chronically with N0-nitro-L-arginine methyl ester (L-NAME; approx, 70 mg l-') and compared to responses in agematched control animals, and age-matched animals after the acute administration of L-NAME (3-100 gtmol kg-1). Parallel experiments examined alterations in responsiveness in rings of trachea and anococcygeus muscles taken from the same animals. 2 Chronic oral administration of L-NAME elevated the blood pressure in anaesthetized animals from 114 ± 5 mmHg to 153 ± 11 mmHg (n = 5). The hypotensive responses to both acetylcholine (1 nmol kg-') and sodium nitroprusside (10 nmol kg-') were enhanced by chronic L-NAME treatment (n = 5-7) whereas acute L-NAME administration enhanced only the response to sodium nitroprusside (n = 5).3 After chronic treatment with L-NAME, the basal perfusion pressure in the isolated perfused kidney was elevated. However, vasodilator responses to either acetylcholine (1 nmol) or sodium nitroprusside (3 nmol) were unaltered (n = 5-7). The vasodilatation induced by acetylcholine was inhibited in a concentration-dependent manner by the administration of acute L-NAME (0.1-100 pM; n = 5), such that significant inhibition was seen at 10 JIM L-NAME. The response to sodium nitroprusside was unaffected by L-NAME. 4 The relaxations of isolated rings of rat thoracic aorta induced by acetylcholine were inhibited in tissues prepared from rats treated chronically with L-NAME (n = 5-7). Acute administration of L-NAME (0.1-100 pM) concentration-dependently inhibited the relaxations induced by acetylcholine in this preparation, with significant inhibition occurring at 1 f1M L-NAME (n = 5). Responses to sodium nitroprusside were unaffected by either chronic or acute exposure to L-NAME (n = 5-7). 5 Relaxations of precontracted anococcygeus muscles induced by electrical field stimulation, or contractions of rings of trachea induced by carbachol or endothelin-1, were unaffected by chronic oral administration of L-NAME (n = 4-6). Acute addition of L-NAME (0.1-100 gM) to the organ baths inhibited in a concentration-dependent manner the relaxations of anococcygeus muscles taken from control animals, with a significant effect being seen at a concentration of 10 f.M (n = 4-6).6 Our cardiovascular data are consistent with chronic oral administration of L-NAME inhibiting the production of nitric oxide (NO) within the vasculature, although the pattern of inhibition is not uniform between different tissues. Despite the inhibition of endothelial NO production, chronic L-NAME does not alter the vasodepressor activity of acetylcholine in vivo or in the isolated perfused kidney. This may be explained by an enhanced responsiveness of guanylyl cyclase pathways, the increased release of vasodilators other than nitric oxide or a decreased importance of nitric oxide in resistance vessels compared with conductance vessels. The resistance of pe...

Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 52%

Comparison of effects of chronic and acute administration of N^G‐nitro‐L‐arginine methyl ester to the rat on inhibition of nitric oxide‐mediated responses

Bryant

Allcock

Warner

1995

“…The lesser mesenteric vasodilator effect of SNP in TG rats was still apparent in the presence of L‐NAME, when there was clear sensitization to the depressor, and renal, mesenteric and hindquarters vasodilator effect of SNP in both strains of rat. If the increase in the haemodynamic effects of SNP in the presence of L‐NAME can be attributed to upregulation of the sensitivity of guanylyl cyclase to exogenous NO, when endogenous NO production is suppressed (Moncada et al , 1991; Gardiner et al , 1993a), then our results provide no evidence of an impairment of this process in TG rats.…”

Section: Discussionmentioning

confidence: 66%

The contribution of nitric oxide to cardiovascular status and responses to vasodilators in conscious, hypertensive, transgenic ((mRen‐2)27) rats

Gardiner

March

Kemp

et al. 1998

1 The aim of the study was to measure the regional haemodynamic responses to vasodilators, and the eects of nitric oxide (NO) synthase inhibition, in conscious, hypertensive, transgenic ((mRen-2)27) rats (TG rats) and normotensive, Hannover Sprague-Dawley (SD) rats. 2 The hypotensive response to acetylcholine was greater in TG than in SD rats, but the renal vasodilator responses were not dierent. 3 The responses to bradykinin were similar in the two strains, except that hindquarters vasodilatation occurred only in SD rats. 4 Salbutamol caused smaller renal and hindquarters vasodilatation in TG rats than in SD rats, and there was mesenteric vasodilatation only in the latter strain. 5 The hypotensive response to sodium nitroprusside was smaller, but the accompanying mesenteric vasodilatation was greater, in SD than in TG rats. 6 The contribution of NO to the vasodilator responses was taken as the dierence between the responses in the presence of the NO synthase inhibitor, N G -nitro-L-arginine methylester (L-NAME), compared to those in the presence of a co-infusion of angiotensin II and vasopressin (to match the haemodynamic eects of L-NAME). 7 In TG rats, L-NAME caused a greater absolute pressor eect, but a smaller mesenteric vasoconstriction, than in SD rats. 8 L-NAME aected the vasodilator responses to all the challenges similarly in the two strains. 9 Collectively, the results provide no direct evidence for impaired NO-mediated vasodilator mechanisms in TG rats. It is feasible that the reduced hindquarters response to bradykinin and the reduced renal and hindquarters responses to salbutamol, in TG rats are due to abnormal b 2 -adrenoceptor-mediated processes.

“…We, and others, have previously reported increased responses to nitrovasodilators in the presence of nonselective NOS inhibition (Moncada et al ., 1991; Gardiner et al ., 1993) and this has been attributed to a supersensitivity at the level of soluble guanylyl cyclase in the absence of endogenous NO (Moncada et al ., 1991). Some augmentation of response might also be expected due to the change in baseline haemodynamic status caused by the NOS inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Comparative regional haemodynamic effects of the nitric oxide synthase inhibitors, S‐methyl‐L‐thiocitrulline and L‐NAME, in conscious rats

Wakefield

March

Kemp

et al. 2003

Self Cite

1 The regional haemodynamic effects of the putative nNOS inhibitor, S-methyl-l-thiocitrulline (SMTC), were compared with those of the nonselective NOS inhibitor, N G -nitro-l-arginine methyl ester (l-NAME), in conscious, male Sprague -Dawley rats. 2 SMTC (0.3 mg kg À1 bolus) produced a significant, short-lived, pressor effect associated with renal, mesenteric and hindquarters vasoconstriction; the same dose of l-NAME did not affect mean blood pressure (BP), although it caused bradycardia and mesenteric vasoconstriction.3 At the highest dose tested (10 mg kg À1 ), l-NAME produced a significantly greater bradycardia and fall in mesenteric vascular conductance than SMTC, although the initial pressor response to SMTC was greater, but less sustained, than that to l-NAME. 4 Infusion of SMTC or l-NAME (3 mg kg À1 h À1) induced rises in BP and falls in renal, mesenteric and hindquarters vascular conductances, but the effects of l-NAME were greater than those of SMTC, and l-NAME also caused bradycardia. 5 The renal vasodilator response to acetylcholine was markedly attenuated by infusion of l-NAME, but unaffected by SMTC. The hindquarters vasodilatation induced by salbutamol was attenuated by l-NAME, but not by SMTC. The mesenteric vasodilator response to bradykinin was modestly enhanced by SMTC, but not by l-NAME. The depressor and renal, mesenteric and hindquarters vasodilator responses to sodium nitroprusside were enhanced by l-NAME, whereas SMTC modestly enhanced the hypotensive and renal vasodilator effects of sodium nitroprusside, but attenuated the accompanying tachycardia. 6 The results are consistent with the cardiovascular effects of low doses of SMTC being attributable to nNOS inhibition.