Losartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats.
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.
Li
P
P
The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1032, USA.
Ferrario
C M
CM
Brosnihan
K B
KB
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology*; D001011:Aorta; D016232:Endothelins / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011982:Receptors, Prostaglandin / Q000187:drug effects; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013777:Tetrazoles / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D016232:Endothelins; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D011982:Receptors, Prostaglandin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C066026:losartan carboxylic acid; D019808:Losartan; D000109:Acetylcholine