Zhang X, Kichuk M R, Mital S, Oz M, Michler R, Nasjletti A, Kaley G, Hintze T H
Department of Physiology and Pharmacology, New York Medical College, Valhalla 10595, USA.
Am J Cardiol. 1999 Aug 19;84(4A):27L-33L. doi: 10.1016/s0002-9149(99)00362-8.
Recently, we found that amlodipine can release nitric oxide (NO) from canine coronary microvessels, which raises the question of whether amlodipine can also promote coronary NO production in failing human hearts. The goal of this study was to define the effect of amlodipine on NO production in failing human hearts and to determine the role of kinins in the control of NO production induced by amlodipine. Six explanted human hearts with end-stage heart failure were obtained immediately at transplant surgery. Coronary microvessels were isolated as previously described, and nitrite, the stable metabolite of NO in aqueous solution, was measured using the Griess Reaction. Amlodipine (10(-10) to 10(-5) mol/L) significantly increased nitrite production in coronary microvessels in a dose-dependent manner. The increase in nitrite in response to the highest dose of amlodipine (79%) was similar in magnitude to either that of the angiotensin-converting enzyme inhibitor ramiprilat (74%) or the neutral endopeptidase inhibitors phosphoramidon (61%) and thiorphan (72%). Interestingly, the increase in nitrite production induced by amlodipine was entirely abolished by N(omega)-nitro-L-arginine methyl ester and also HOE-140 (a bradykinin-2 antagonist) and dichloroisocoumarin (a serine protease inhibitor that blocks kallikrein activity). These results indicate that amlodipine can promote coronary NO production in failing human hearts and that this effect is dependent on a kinin-mediated mechanism.
最近，我们发现氨氯地平可使犬冠状动脉微血管释放一氧化氮（NO），这就引出了一个问题：氨氯地平是否也能促进衰竭人心脏中的冠状动脉NO生成。本研究的目的是确定氨氯地平对衰竭人心脏中NO生成的影响，并确定激肽在控制氨氯地平诱导的NO生成中的作用。在移植手术时立即获取6个终末期心力衰竭的离体人心脏。如前所述分离冠状动脉微血管，使用格里斯反应测定亚硝酸盐（水溶液中NO的稳定代谢产物）。氨氯地平（10^(-10)至10^(-5)mol/L）以剂量依赖方式显著增加冠状动脉微血管中的亚硝酸盐生成。对最高剂量氨氯地平的亚硝酸盐增加量（79%）在幅度上与血管紧张素转换酶抑制剂雷米普利拉（74%）或中性内肽酶抑制剂磷酰胺素（61%）和硫磷酰胺（72%）相似。有趣的是，氨氯地平诱导的亚硝酸盐生成增加被N(ω)-硝基-L-精氨酸甲酯以及HOE-140（一种缓激肽-2拮抗剂）和二氯异香豆素（一种阻断激肽释放酶活性的丝氨酸蛋白酶抑制剂）完全消除。这些结果表明氨氯地平可促进衰竭人心脏中的冠状动脉NO生成，且这种作用依赖于激肽介导的机制。
