Satake N, Imanishi M, Keto Y, Ishikawa M, Yamada H, Shibata S, Tomiyama A
Department of Pharmacology, University of Hawaii, School of Medicine, Honolulu 96822, USA.
J Cardiovasc Pharmacol. 2000 Mar;35(3):457-67. doi: 10.1097/00005344-200003000-00017.
The vasoinhibitory effect of KT3-671, a recently synthesized nonpeptide angiotensin II (Ang II), AT1-receptor antagonist, and the factors affecting insurmountable antagonism of Ang II were examined in rabbit and rat isolated vascular smooth muscle preparations. In rabbit and rat aortic rings, KT3-671 caused insurmountable antagonism of Ang II. In addition, KT3-671 inhibited contractile responses to angiotensin III (Ang III). In rabbit isolated smooth muscles, KT3-671 was most effective in reducing the maximal contraction induced by Ang II in the renal artery followed by the basilar artery and the aorta. In rat renal arterial rings, KT3-671 (10(-5) M) inhibited the concentration-response curves of prostaglandin F2alpha and STA2. In rabbit and rat aortic rings without endothelium, the insurmountable antagonisms 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, KT3-671 abolished the inhibitory effect of CV- 11974 in the rat aorta but not in the 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 enhanced the insurmountable antagonism by KT3-671. ODQ (3 x 10(-6) M), N(G)-nitro-L-arginine (3 x 10(-4) M), 4-aminopyridine (3 x 10(-3) M), tetraethylammonium (TEA; 10(-3) M), or iberiotoxin (10(-7) M) did not affect the inhibitory action of KT3-671 or CV-11974. Methylene blue (3 x 10(-6) M), KCl (10(2) M), TEA (10(-2) M), or BaC12 (10(-4) M) changed the insurmountable antagonism by KT3-671 to surmountable antagonism and abolished the inhibitory effect of CV-11974. However, glibenclamide (3 x 10(-6) M) did not affect the inhibitory 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 suggest that K(ATP) channels may be involved in insurmountable antagonism of Ang II by KT3-671 and CV-11974. Key Words: KT3-671-Rabbit-Rat-Vascular smooth muscle-Angiotensin II-Insurmountable antagonist-K(TP)channels.
在兔和大鼠离体血管平滑肌标本中，研究了最近合成的非肽类血管紧张素II（Ang II）AT1受体拮抗剂KT3 - 671的血管抑制作用以及影响Ang II不可逾越性拮抗作用的因素。在兔和大鼠主动脉环中，KT3 - 671引起了Ang II的不可逾越性拮抗作用。此外，KT3 - 671抑制了对血管紧张素III（Ang III）的收缩反应。在兔离体平滑肌中，KT3 - 671在降低肾动脉中由Ang II诱导的最大收缩方面最有效，其次是基底动脉和主动脉。在大鼠肾动脉环中，KT3 - 671（10⁻⁵ M）抑制了前列腺素F2α和STA2的浓度 - 反应曲线。在无内皮的兔和大鼠主动脉环中，KT3 - 671和EXP 3174对Ang II的不可逾越性拮抗作用分别通过用DuP 753和KT3 - 671预处理而变为可逾越性拮抗作用。此外，KT3 - 671消除了CV - 11974对大鼠主动脉的抑制作用，但对兔主动脉无此作用。吲哚美辛（10⁻⁵ M）或去除内皮并不影响CV - 11974或EXP 3174对Ang II的抑制作用，但增强了KT3 - 671的不可逾越性拮抗作用。ODQ（3×10⁻⁶ M）、N(G)-硝基 - L - 精氨酸（3×10⁻⁴ M）、4 - 氨基吡啶（3×10⁻³ M）、四乙铵（TEA；10⁻³ M）或iberiotoxin（10⁻⁷ M）不影响KT3 - 671或CV - 11974的抑制作用。亚甲蓝（3×10⁻⁶ M）、KCl（10² M）、TEA（10⁻² M）或BaC12（10⁻⁴ M）将KT3 - 671的不可逾越性拮抗作用变为可逾越性拮抗作用，并消除了CV -
