Vol. 281, Issue 3, 1065-1070, 1997

Nonpeptide Angiotensin II Antagonist Losartan Inhibits Thromboxane A₂-Induced Contractions in Canine Coronary Arteries¹

Ping Li, Carlos M. Ferrario and K. Bridget Brosnihan

The Hypertension Center, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina

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 vasoconstriction in coronary rings (EC₅₀, 10.6 ± 0.9 nmol/l). Pretreatment with losartan (10⁸-10⁵ 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 µmol/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 µmol/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 µmol/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.