The inhibitory effect of KT3-671, a nonpeptide angiotensin-receptor antagonist, on rabbit and rat isolated vascular smooth muscles: A possible involvement of K-ATP channels

The vasoinhibitory effect of KT3-671, a recently synthesized nonpeptide ang iotensin II (Ang II), AT(1)-receptor antagonist, and the factors affecting insurmountable antagonism of Ang II were examined in rabbit and rat isolate d vascular smooth muscle preparations. In rabbit and rat aortic rings, KT3- 671 caused insurmountable antagonism of Ang II. In addition, KT3-671 inhibi ted contractile responses to angiotensin III (Ang III). In rabbit isolated smooth muscles, KT3-671 was most effective in reducing the maximal contract ion induced by Ang LI in the renal artery followed by the basilar artery an d the aorta, In rat renal arterial rings, KT3-671 (10(-5) M) inhibited the concentration-response curves of prostaglandin F-2 alpha and STA(2). In rab bit and rat aortic rings without endothelium, the insurmountable antagonism s of Ang II by KT3-671 and EXP 3174 were changed to surmountable antagonism by pretreatment with DuP 753 and KT3-671 respectively. In addition, KT3-67 1 abolished the inhibitory effect of CV-11974 in the rat aorta but not in t he rabbit aorta. Indomethacin (10(-5) M) or the removal of endothelium did not affect the inhibitory effect of Ang II by CV-11974 or EXP 3174 but enha nced the insurmountable antagonism by KT3-671. ODQ (3 x 10(-6) M), N-G-nitr o-L-arginine (3 x 10(-4) M), 4-aminopyridine (3 x 10(-3) M), tetraethylammo nium (TEA; 10(-3) M), or iberiotoxin (10(-7) M) did not affect the inhibito ry action of KT3-671 or CV-11974. Methylene blue (3 x 10(-6) M), KCI (10(-2 ) M), TEA (10(-2) M), or BaCl, (10(-4) M) changed the insurmountable antago nism by KT3-671 to surmountable antagonism and abolished the inhibitory eff ect of CV-11974. However, glibenclamide (3 x 10(-6) M) did not affect the i nhibitory action of KT3-671 but reduced the insurmountable antagonism by CV -11974. These results indicate that KT3-671 is an insurmountable antagonist of Ang II in the rabbit and rat aorta, The results in the rat aorta also s uggest that K-ATP, channels may be involved in insurmountable antagonism of Ang by KT3-671 and CV-11974.