Antagonistic Effects of Losartan on Thromboxane A2-Receptors in Human Isolated Gastroepiploic Artery and Saphenous Vein

Abstract

In addition to its AT1-receptor antagonist activity, losartan has been shown to antagonize thromboxane A2 (TXA2)-induced contraction of animal vessels. We investigated for the first time in human isolated gastroepiploic artery (GEA) and saphenous vein (SV) the TXA2/PGH2-receptor antagonist activity of losartan in the presence of indomethacin (1 microM) and N(omega)-nitro-L-arginine (100 microg). Losartan at concentrations of > or =1 microM on GEA and from 10 microM on SV significantly shifted U46619-induced contractions to the right. In addition, 100 microM losartan decreased by 34% the amplitude of the contraction to U46619 on both GEA and SV. The potency of losartan for the TXA2 receptor was 50- and 80-fold lower than that for the AT1 receptor on human GEA and SV, respectively. This inhibitory effect of losartan appeared selective for angiotensin II and TXA2-induced contractions because 100 microM losartan did not modify either endothelin-1- or KCl-induced contraction in human SV, although a reduction of norepinephrine- and 5-hydroxytryptamine-induced contraction was observed in human GEA and SV, respectively. In conclusion, losartan is an antagonist of TXA2 receptor on human GEA and SV. However, this antagonist activity occurred for a relative high dose of losartan, suggesting that it contributes at a low level, if any, to its antihypertensive effect.

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

“…16 It was also important to evaluate any endogenous participation of prostanoids in AT 1 -As-stimulated NO release, because losartan has been shown to increase the dose-dependent release of PGI 2 in vascular smooth muscle cells. 24 However, our data presented here demonstrated that neither SQ29,548, a selective TXA 2 / PGH 2 -receptor antagonist, nor indomethacin, an inhibitor of cyclooxygenase synthase, affected AT 1 -As-stimulated NO release in platelets and endothelial cells.…”

“…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. The limitation of these studies is that the release of NO from endothelium could be suggested on the basis of the comparison of vessel relaxation.…”