Nonpeptide angiotensin II antagonist losartan inhibits thromboxane A2-induced contractions in canine coronary arteries.
We investigated the selectivity of a nonpeptide angiotensin II AT1 receptor antagonist losartan for the vascular thromboxane A2 (TxA2)/prostaglandin endoperoxide (PGH2) receptor in canine coronary arteries. Isometric tension was measured in canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2. The TxA2 analog, U46619, produced dose-dependent vasoconstdction in coronary rings (EC50, 10.6 +/- 0.9 nmol/l). Pretreatment with losartan (10(-8)-10(-5) mol/l) inhibited the contractile response of U46619 and shifted the concentration-response curve to the right in dose-dependent manner. The EC50 of U46619 was increased 3- and 13-fold in the presence of both 1 and 10 micromol/l of losartan without a change in maximal contraction. The selective TxA2/PGH2 receptor antagonist SQ29548 blocked U46619-induced contraction with greater potency than losartan in isolated coronary arteries. The active metabolite of losartan EXP3174 at 1 micromol/l did competitively block U46619-induced contractions in canine coronary rings. In contrast, the contractile responses produced by U46619 were unaffected by exposure to the nonpeptide AT1 receptor antagonist CV11974, the AT2 receptor antagonist PD123319 or the nonselective peptide angiotensin II antagonist Sar1Thr8-Ang II, each at 1 micromol/l concentration. These data indicate that losartan and its active metabolite EXP3174 are antagonists to the TxA2/PGH2 receptor in canine coronary arteries. The antagonistic effect of losartan and EXP3174 on the vascular TxA2/ PGH2 receptor may contribute to the long-term blood pressure-lowering effects of angiotensin antagonists in hypertension.
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The Hypertension Center, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1032, USA.
Ferrario
C M
CM
Brosnihan
K B
KB
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D013928:Thromboxane A2; D019808:Losartan