Role of Nitric Oxide in the Control of Cardiac Oxygen Consumption in B 2 -Kinin Receptor Knockout Mice

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Abstract
—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 (MV̇ o 2 ) via a B 2 -kinin receptor/nitric oxide–dependent mechanism. Left ventricular free wall and septum were isolated from normal and B 2 -kinin receptor knockout (B 2 −/−) mice. Myocardial tissue oxygen consumption was measured in an airtight chamber with a Clark-type oxygen electrode. Baseline MV̇ o 2 was not significantly different between normal (239±13 nmol of O 2 · min −1 · g −1 ) and B 2 −/− (263±24 nmol of O 2 · 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 B 2 −/− 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 B 2 −/− 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 MV̇ o 2 in normal mice. At the highest concentration, tissue O 2 consumption was decreased by 18±3%, 20±5%, and 28±3%, respectively. The reduction in MV̇ o 2 to all 3 drugs was attenuated in the presence of N G -nitro- l -arginine-methyl ester. However, in the B 2 −/− mice, bradykinin, ramiprilat, and amlodipine had virtually no effect on MV̇ o 2 . Therefore, nitric oxide, through a bradykinin-receptor–dependent mechanism, regulates cardiac oxygen consumption. This physiological mechanism is absent in B 2 −/− mice and may be evidence of an important therapeutic mechanism of action of angiotensin-converting enzyme inhibitors and amlodipine.