title: Bioenergetics in cardiac hypertrophy: mitochondrial respiration as a pathological target of NO*.
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.
authors.affiliation: Departmentof Pathology and Center for Free Radical Biology, University of Alabama at Birmingham, 35294, USA.
authors.forename: L
authors.initials: L
authors.lastname: Dai
authors.forename: P S
authors.initials: PS
authors.lastname: Brookes
authors.forename: V M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.forename: P G
authors.initials: PG
authors.lastname: Anderson
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D019069:Cell Respiration / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D019335:Nitroarginine / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat