Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

Abstract

Background — Endogenous nitric oxide (NO) has been reported to inhibit oxygen consumption in the normal heart, so that nonselective inhibition of NO synthase (NOS) caused an increase of myocardial oxygen consumption (MV̇O 2 ). Although endothelial NOS responses are depressed in congestive heart failure (CHF), inducible NOS (iNOS) may be expressed in failing myocardium. Methods and Results — This study tested the hypothesis that NOS inhibition would increase MV̇O 2 in the failing heart. CHF was produced in dogs by use of the rapid ventricular pacing model. In comparison with normal values, animals with CHF had reduced coronary blood flow and MV̇O 2 at rest, with a blunted response to treadmill exercise. Selective iNOS inhibition with S -methylisothiourea (1.5 mg/kg IC) increased left ventricular systolic pressure and left ventricular dP/dt and caused an increase in MV̇O 2 at rest and during exercise ( P <0.05), with a parallel upward shift in the relationship between MV̇O 2 and rate-pressure product. In contrast, S -methylisothiourea had no effect on MV̇O 2 or coronary flow in normal animals, although nonselective NOS inhibition with N G -nitro- l -arginine did cause an increase of MV̇O 2 in normal and in CHF animals. Conclusions — The results indicate that endogenous NO can modulate MV̇O 2 in failing hearts, but unlike the normal heart, this NO appears to be produced, at least in part, by iNOS.