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

Academic Article

Abstract

  • 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* (IC(50) 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.
  • Keywords

  • Amidines, Animals, Benzylamines, Cardiomegaly, Cell Respiration, Energy Metabolism, Enzyme Inhibitors, Male, Mitochondria, Muscle Fibers, Skeletal, Myocardial Contraction, Myocardium, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Nitroarginine, Oxidative Phosphorylation, Rats, Rats, Sprague-Dawley
  • Digital Object Identifier (doi)

    Author List

  • Dai L; Brookes PS; Darley-Usmar VM; Anderson PG
  • Start Page

  • H2261
  • End Page

  • H2269
  • Volume

  • 281
  • Issue

  • 6