Investigation of the inhibitory effect of N^G‐nitro‐L‐arginine methyl ester on the antihypertensive effect of the angiotensin AT₁ receptor antagonist, GR138950

Abstract

1 The eect of systemic administration of the nitric oxide synthase inhibitor, N G -nitro-L-arginine methyl ester (L-NAME) on the antihypertensive eects of the angiotensin AT 1 receptor antagonist, GR138950, the angiotensin-converting enzyme (ACE) inhibitor, enalapril, or hydralazine has been evaluated in unrestrained, conscious renal artery ligated hypertensive (RALH) rats. The eect of the phosphodiesterase type V inhibitor, zaprinast on the antihypertensive eect of GR138950 in RALH rats was also examined. The eect of GR138950 on blood pressure, and plasma and urine cyclic GMP levels was compared to that of zaprinast in conscious RALH rats. 2 GR138950, enalapril or hydralazine caused marked reductions in blood pressure associated with immediate tachycardia in conscious RALH rats. L-NAME pretreatment attenuated the antihypertensive eects of GR138950 or enalapril but not that of hydralazine in conscious RALH rats. The initial tachycardia caused by GR138950 or enalapril but not hydralazine was attenuated by L-NAME pretreatment. L-NAME alone caused a transient (20 min) pressor response and a prolonged (6 h) bradycardia in conscious RALH rats. 3 Pretreatment with indomethacin did not aect the cardiovascular eect of GR138950 in conscious RALH rats. Indomethacin alone did not signi®cantly change basal blood pressure or heart rate in RALH rats. 4 Zaprinast pretreatment did not aect the antihypertensive eect of GR138950 in conscious RALH rats but potentiated the depressor response to sodium nitroprusside. Zaprinast alone caused a small reduction in basal blood pressure but did not change basal heart rate in RALH rats. 5 The antihypertensive eect of GR138950 was not associated with an increase in plasma or urine cyclic GMP levels in conscious RALH rats, whereas zaprinast caused a small fall in blood pressure associated with increases in plasma and urine cyclic GMP. 6 The ability of L-NAME to inhibit the antihypertensive action of GR138950 or enalapril suggests that these agents release nitric oxide (NO) and/or enhance the cardiovascular eects of NO as part of their mechanism of action. However, the inability of zaprinast to potentiate the antihypertensive eects of GR138950 and the ®nding that GR138950 did not increase urine and plasma cyclic GMP levels are not consistent with this view. Attenuation of the response to GR138950 or enalapril, but not hydralazine, suggests a selective interaction between L-NAME and inhibitors of the renin-angiotensin system, although the nature of this interaction is unknown.

The antihypertensive profile of the angiotensin AT1 receptor antagonist, GR138950, and the influence of potential homeostatic compensatory mechanisms in renal hypertensive rats

“…Rats were individually housed and maintained under a 12 : 12h light‐dark cycle (lights on at 06.00 h) with free access to food and water. Surgery was performed in two stages with 5 days between each stage and is described in detail elsewhere (Anderson & Drew, 1997). Briefly, renal hypertension was induced in all animals by ligation of the left renal artery.…”

“…However, the time‐course of its antihypertensive effect in renal hypertensive rats (maximum fall in blood pressure occurs after 5–7 h) does not coincide with that of its antagonist profile against exogenous angiotensin I or angiotensin II‐induced pressor responses in normotensive rats (maximal rightward shift of the dose‐pressor response to angiotensin I or angiotensin II occurs at 1 h (Hilditch et al , 1995, 1996). Furthermore, the fall in blood pressure produced by GR138950 seems to occur in two phases; the first, rapidly developing phase occurs over the 30–60 min following systemic administration, and the second phase develops slowly and progressively reaching its nadir 7 h or more after administration (Anderson & Drew, 1997). A similar profile of action has been noted for some other AT 1 receptor antagonists, notably L‐158,809 and EXP3174 which, like GR138950, do not depend upon metabolism for their activity (Hodges et al , 1992).…”