Antagonistic effects of losartan on thromboxane A2-receptors in human isolated gastroepiploic artery and saphenous vein

In addition to its AT(1)-receptor antagonist activity, losartan has been shown to antagonize thromboxane A(2) (TXA(2))-induced contraction of animal vessels. We investigated for the first time in human isolated gastroepiploic artery (GEA) and saphenous vein (SV) the TXA(2)/PGH(2)-receptor antagonist activity of losartan in the presence of indomethacin (1 mu M) and N-omega-nitro-L-arginine (100 mu M). Losartan at concentrations of greater than or equal to 1 mu M on GEA and from 10 mu M on SV significantly shifted U46619-induced contractions to the right. In addition. 100 mu M losartan decreased by 34% the amplitude of the contraction to U46619 on both GEA and SV. The potency of losartan for the TXA(2) receptor was 50- and 80-fold lower than that for the AT(1) receptor on human GEA and SV, respectively. This inhibitory effect of losartan appeared selective for angiotensin II and TXA(2)-induccd contractions because 100 mu M 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 an tagonist of TXA(2) 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.