Bioenergetics in cardiac hypertrophy:: mitochondrial respiration as a pathological target of NO•

A rat aortic banding model of cardiac hypertrophy was used to test the hypothesis that reversible inhibition of mitochondrial respiration by nitric oxide (NO .) elicits a bioenergetic defect in the hypertrophied heart. In support of this hypothesis, the respiration of myocytes isolated from hypertrophied hearts was more sensitive to exogenous NO . (IC50 200 +/- 10 nM vs. 290 +/- 30 nM in controls, P=0.0064). Hypertrophied myocytes also exhibited significantly elevated inducible NO . synthase (iNOS). Consistent with this endogenous source for NO ., the respiration of hypertrophied myocytes was significantly inhibited at physiological O-2 tensions versus controls. Both the nonspecific NOS inhibitor nitro-L-arginine and the iNOS-specific inhibitor N-[3-(aminomethyl)-benzyl] acetamidine . 2HCl reversed this inhibition, with no effect on respiration of control myocytes. Consistent with an NO . -mediated mitochondrial dysfunction, the ability of intact perfused hearts to respond to a pacing workload was impaired in hypertrophy, and this effect was reversed by NOS inhibition. We conclude that endogenously generated NO . can modulate mitochondrial function in the hypertrophied heart and suggest that this bioenergetic defect may underlie certain pathological features of hypertrophy.