Role of Nitric Oxide in the Control of Cardiac Oxygen Consumption in B2-Kinin Receptor Knockout Mice

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 (MO2) 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 MO2 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 MO2 in normal mice. At the highest concentration, tissue O2 consumption was decreased by 18±3%, 20±5%, and 28±3%, respectively. The reduction in MO2 to 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 MO2. 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. © 1999 Lippincott Williams & Wilkins, Inc.