Nitric Oxide and Prostaglandins in the Prolonged Effects of Losartan and Ramipril in Hypertension

Abstract

We investigated the role of endogenous nitric oxide, kinins, and prostaglandins in the vasodepressor and renal excretory effects of the angiotensin II receptor antagonist losartan and the angiotensin-converting enzyme inhibitor ramipril administered for 1 week to spontaneously hypertensive rats. To this end, either losartan (10 mg/kg per day) or ramipril (2.5 mg/kg per day) was administered in drinking water with or without simultaneous administration of (1) the nitric oxide synthesis inhibitor Ng-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg per day), (2) the cyclooxygenase inhibitor indomethacin (5 mg/kg per day), (3) the bradykinin B2 receptor antagonist Hoe 140 (0.5 mg/kg per day SC), or (4) L-NAME plus indomethacin. Both losartan and ramipril significantly reduced blood pressure as measured by the tail-cuff method. L-NAME increased blood pressure when administered solely or in combination with losartan. However, L-NAME attenuated the hypotensive effect of ramipril. Indomethacin did not affect blood pressure but it reduced the antihypertensive action of losartan and ramipril. Indomethacin administration did not potentiate the increase in blood pressure induced by L-NAME. However, the concurrent administration of both inhibitors almost totally blunted the vasodepressor action of ramipril. By contrast, losartan administration in the presence of L-NAME and indomethacin increased blood pressure to a level similar to that after losartan plus L-NAME. Hoe 140 did not modify either blood pressure or the hypotensive effects of losartan or ramipril. Increases in diuresis and water intake were observed during ramipril administration. Both effects were blunted only with the concurrent administration of L-NAME and indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

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

“…Recent studies have shown that losartan can increase production of vasodilator prostaglandins (Jaiswal et al, 1991) which contribute to the antihypertensive action of this AT 1 receptor antagonist (Cachofeiro et al, 1995). In the present study, the antihypertensive response to GR138950 was not aected by indomethacin, suggesting that prostaglandin production was not required for the response of GR138950 in rats with renin-dependent hypertension.…”

Angiotensin Subtype 1 Receptor (AT1) Blockade Improves Vasorelaxation in Heart Failure by Up-Regulation of Endothelial Nitric-Oxide Synthase via Activation of the AT2Receptor

“…This effect appears to be associated with an up-regulation of eNOS, which has been previously described with AT 2 receptor stimulation (Weimer et al, 1993;Cachofeiro et al, 1995;Maseo et al, 1996). We speculated that, since candesartan selectively inhibits AT 1 receptors, it has the potential to promote selective binding of angiotensin II to the free AT 2 receptors, effectively leading to AT 2 receptor stimulation and potential up-regulation of eNOS.…”

“…Given the ability of ANG II to promote endothelial NO synthesis through the stimulation of the angiotensin subtype 2 receptor (AT 2 ) (Weimer et al, 1993;Olson et al, 1997;Hennington et al, 1998), we speculated that angiotensin receptor blockade could improve endothelial-dependent vasodilation, at least in part, via NO. This hypothesis is based on data in hypertensive animal models showing that AT 1 receptor antagonism restores impaired NO-mediated endothelial vasorelaxation (Cachofeiro et al, 1995;Maseo et al, 1996). Further-more, stimulation of the AT 2 receptors by unbound ANG II has been reported to induce vasodilation (Maseo et al, 1996).…”

Angiotensin II AT 1 Receptor Antagonists Inhibit Platelet Adhesion and Aggregation by Nitric Oxide Release

“…12 Likewise, the involvement of endothelium-derived NO has been suggested in the mechanism of the blood pressure-lowering action of losartan in rats in long-term treatment. 13,14 The chronic treatment of stroke-prone SHR with losartan increased aortic cyclic GMP content. Maeso et al 23 reported that losartan reduced constrictor responses to phenylephrine in blood vessels of SHR by stimulating production of NO, and this effect might be partially mediated through blockage of Ang II T 2 -type receptors by the AT 1 -As.…”

“…In this regard, it has been reported that administration of NO synthesis inhibitors impairs the blood pressure-lowering action induced by losartan in rats in both short-term 12 and longer treatments. 13,14 The results from the in vitro studies performed directly on isolated vessels are less consistent regarding the action of AT 1 -As, which could involve enhanced NO release from endothelial cells. Although the preincubation of rat aortic rings with losartan reduced the contractile response to TXA 2 analog (U46619), and this action was reversed by N G -nitro-L-arginine methyl ester (L-NAME), 15 no influence of NOS inhibition on the cessation of U46619 effect by losartan in human gastroepiploic artery and saphenous vein, 16 as well as irbesartan in canine coronary arteries, 9 was observed.…”