9700980

pubmed:Citation

2

Our recent studies have shown that the nonpeptide angiotensin II (Ang II) antagonist losartan interacts with thromboxane A2/prostaglandin H2 receptors and inhibits the thromboxane A2 (TxA2) analog U46619-induced vasoconstriction in canine coronary arteries. In this study, we further investigated whether losartan prevents TxA2-induced platelet aggregation and vasoconstriction in spontaneously hypertensive rats (SHRs). Pretreatment with losartan (10 microM) significantly reduced U46619-induced, concentration-dependent washed platelet aggregation. The inhibition is specific for losartan, because another Ang II AT1-receptor antagonist, CV11974 (10 microM), an active metabolite of TCV116, did not block the platelet aggregation caused by U46619. In addition, losartan (10 microM) augmented acetylcholine (ACH)-induced nitric oxide (NO)-dependent vasodilation and abolished the ACH-induced endothelium-derived contracting factor (EDCF)-mediated vasoconstriction in the aortic rings from adult SHRs. U46619 produced dose-dependent vasoconstriction in aortic vessels of SHRs, which was demonstrated to be blocked by the potent, selective TxA2/PGH2 receptor antagonist SQ29,548. Pretreatment with losartan (10(-6)-10(-5) M) inhibited the contractile response of U46619 and shifted the concentration-response curve to the right in a dose-dependent manner. The effective concentration at half maximal contraction (EC50) of U46619 was increased 2.5- and 7.6-fold in the presence of 1 and 10 microM losartan, respectively, without changes in maximal contraction. The active metabolite of losartan, EXP3174, at 1 microM also competitively inhibited U46619-induced contractions in aortic rings of SHRs. In contrast, neither the AT1-receptor antagonist CV11974, the AT2 antagonist PD123319, nor the angiotensin-converting enzyme inhibitor lisinopril, each at concentrations of 1 microM, had any effect on the U46619-induced constriction in aortic rings. In conclusion, losartan, acting as both AT1- and TxA2/PGH2-receptor antagonists, may enhance its therapeutic profile in the treatment of hypertension and cardiovascular disease.

eng

IM

MEDLINE

0160-2446

Print

NLM

198-205

pubmed-meshheading:9700980-15-Hydroxy-11 alpha,9..., pubmed-meshheading:9700980-Acetylcholine, pubmed-meshheading:9700980-Angiotensin II, pubmed-meshheading:9700980-Animals, pubmed-meshheading:9700980-Antihypertensive Agents, pubmed-meshheading:9700980-Aorta, pubmed-meshheading:9700980-Endothelins, pubmed-meshheading:9700980-Endothelium, Vascular, pubmed-meshheading:9700980-Imidazoles, pubmed-meshheading:9700980-Losartan, pubmed-meshheading:9700980-Male, pubmed-meshheading:9700980-Platelet Aggregation, pubmed-meshheading:9700980-Platelet Aggregation Inhibitors, pubmed-meshheading:9700980-Rats, pubmed-meshheading:9700980-Rats, Inbred SHR, pubmed-meshheading:9700980-Receptors, Prostaglandin, pubmed-meshheading:9700980-Receptors, Thromboxane A2, Prostaglandin H2, pubmed-meshheading:9700980-Tetrazoles, pubmed-meshheading:9700980-Thromboxane A2, pubmed-meshheading:9700980-Vasoconstriction, pubmed-meshheading:9700980-Vasoconstrictor Agents

Losartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't