Nitric oxide modulates myocardial oxygen consumption in the failing heart

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 (MV̇O₂). 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 MV̇O₂ 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 MV̇O₂ 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 MV̇O₂ at rest and during exercise (P<0.05), with a parallel upward shift in the relationship between MV̇O₂ and rat-pressure product. In contrast, S-methylisothiourea had no effect on MV̇O₂ or coronary flow in normal animals, although nonselective NOS inhibition with N^G-nitro-L-arginine did cause an increase of MV̇O₂ in normal and in CHF animals. Conclusions - The results indicate that endogenous NO can modulate MV̇O₂ in failing hearts, but unlike the normal heart, this NO appears to be produced, at least in part, by iNOS.