Synergy of amlodipine and angiotensin-converting enzyme inhibitors in regulating myocardial oxygen consumption in normal canine and failing human hearts

The production of endogenous nitric oxide, which regulates myocardial oxyge n consumption, is decreased in heart failure. As with angiotensin-convertin g enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kini n-mediated nitric oxide production in coronary microvessels. We investigate d the possibility of synergy between ACE inhibitors and amlodipine in regul ating myocardial oxygen consumption. Left ventricular myocardium was isolat ed from 6 healthy dog hearts and 5 human hearts with end-stage heart failur e at the time of orthotopic heart transplantation. Myocardial oxygen consum ption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE in hibitor), amlodipine, and the combination of a sub-threshold dose of ramipr ilat (10(-8) mol/L) + amlodipine. These experiments were repeated with L-ni tro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B-2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canin e hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-depende nt reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and am lodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxyge n consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption wa s 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared wit h amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated b y L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE in hibitors and amlodipine act synergistically to regulate myocardial oxygen c onsumption by modulating kinin-mediated nitric oxide release, and this comb ination of drugs may be useful in the treatment of heart failure. (C)1999 b y Excerpta Medica, Inc.