The aim of this study was to determine whether bradykinin, the angiotensin-converting enzyme inhibitor ramiprilat, and the calcium-channel antagonist amlodipine reduce myocardial oxygen consumption (M&OV0312;O2) via a B2-kinin receptor/nitric oxide-dependent mechanism. Left ventricular free wall and septum were isolated from normal and B2-kinin receptor knockout (B2−/−) mice. Myocardial tissue oxygen consumption was measured in an airtight chamber with a Clark-type oxygen electrode. Baseline M&OV0312;O2was not significantly different between normal (239±13 nmol of O2· min−1· g−1) and B2−/− (263±24 nmol of O2· min−1· g−1) mice. S-nitroso-N-acetyl-penicillamine (10−7to 10−4mol/L) reduced oxygen consumption in a concentration-dependent manner in both normal (maximum, 36±3%) and B2−/− mice (28±3%). This was also true for the endothelium-dependent vasodilator substance P (10−10to 10−7mol/L; 22±7% in normal mice and 20±4% in B2−/− mice). Bradykinin (10−7to 10−4mol/L), ramiprilat (10−7to 10−4mol/L), and amlodipine (10−7to 10−5mol/L) all caused concentration-dependent decreases in M&OV0312;O2in normal mice. At the highest concentration, tissue O2consumption was decreased by 18±3%, 20±5%, and 28±3%, respectively. The reduction in M&OV0312;O2to all 3 drugs was attenuated in the presence of NG-nitro-L-arginine-methyl ester. However, in the B2−/− mice, bradykinin, ramiprilat, and amlodipine had virtually no effect on M&OV0312;O2. Therefore, nitric oxide, through a bradykinin-receptor-dependent mechanism, regulates cardiac oxygen consumption. This physiological mechanism is absent in B2−/− mice and may be evidence of an important therapeutic mechanism of action of angiotensin-converting enzyme inhibitors and amlodipine.