Amlodipine promotes kinin-mediated nitric oxide production in coronary microvessels of failing human hearts

Recently, we found that amlodipine can release nitric oxide (NO) from canin e coronary microvessels, which raises the question of whether amlodipine ca n 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 faili ng human hearts and to determine the role of kinins in the control of NO pr oduction induced by amlodipine. Six explanted human hearts with end-stage h eart failure were obtained immediately at transplant surgery. Coronary micr ovessels were isolated as previously described, and nitrite, the stable met abolite of NO in aqueous solution, was measured using the Griess Reaction. Amlodipine (10(-10) to 10(-5) mol/L) significantly increased nitrite produc tion in coronary microvessels in a dose-dependent manner. The increase in n itrite in response to the-highest dose of amlodipine (79%) was similar in m agnitude to either that of the angiotensin-converting enzyme inhibitor rami prilat (74%) or the neutral endopeptidase inhibitors phosphoramidon (61%) a nd thiorphan (72%). Interestingly, the increase in nitrite production induc ed 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 result s indicate that amlodipine can promote coronary NO production in failing hu man hearts and that this effect is dependent on a kinin-mediated mechanism. (C) 1999 by Excerpta Medica, Inc.