—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 (MV̇o₂) 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 MV̇o₂ was 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 (10⁻⁷ to 10⁻⁴ mol/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 (10⁻¹⁰ to 10⁻⁷ mol/L; 22±7% in normal mice and 20±4% in B₂ −/− mice). Bradykinin (10⁻⁷ to 10⁻⁴ mol/L), ramiprilat (10⁻⁷ to 10⁻⁴ mol/L), and amlodipine (10⁻⁷ to 10⁻⁵ mol/L) all caused concentration-dependent decreases in MV̇o₂ in normal mice. At the highest concentration, tissue O₂ consumption was decreased by 18±3%, 20±5%, and 28±3%, respectively. The reduction in MV̇o₂ to all 3 drugs was attenuated in the presence of N^G-nitro-l-arginine-methyl ester. However, in the B₂ −/− mice, bradykinin, ramiprilat, and amlodipine had virtually no effect on MV̇o₂. 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.