(Circulation. 1999;100:1291-1297.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Nitric Oxide Modulates Mitochondrial Respiration in Failing Human Heart
From the Department of Physiology, New York Medical College, Valhalla, NY (K.E.L., S.K.L., M.S.W., R.B., G.K., T.H.H.), and Columbia University, College of Physicians and Surgeons, New York, NY (S.M., M.O., L.A.).
Correspondence to Thomas H. Hintze, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas_Hintze{at}nymc.edu
Background—Our objective for this study was to investigate whether nitric oxide (NO) modulates tissue respiration in the failing human myocardium.
Methods and Results—Left ventricular free wall and right ventricular tissue samples were taken from 14 failing explanted human hearts at the time of transplantation. Tissue oxygen consumption was measured with a Clark-type oxygen electrode in an airtight stirred bath containing Krebs solution buffered with HEPES at 37°C (pH 7.4). Rate of decrease in oxygen concentration was expressed as a percentage of the baseline, and results of the highest dose are indicated. Bradykinin (10-4 mol/L, -21±5%), amlodipine (10-5 mol/L, -14±5%), the ACE inhibitor ramiprilat (10-4 mol/L, -21±2%), and the neutral endopeptidase inhibitor thiorphan (10-4 mol/L, -16±5%) all caused concentration-dependent decreases in tissue oxygen consumption. Responses to bradykinin (-2±6%), amlodipine (-2±4%), ramiprilat (-5±6%), and thiorphan (-4±7%) were significantly attenuated after NO synthase blockade with N-nitro-L-arginine methyl ester (10-4 mol/L; all P<0.05). NO-releasing compounds S-nitroso-N-acetyl-penicillamine (10-4 mol/L, -34±5%) and nitroglycerin (10-4 mol/L, -21±5%), also decreased tissue oxygen consumption in a concentration-dependent manner. However, the reduction in tissue oxygen consumption in response to S-nitroso-N-acetyl-penicillamine (-35±7%) or nitroglycerin (-16±5%) was not significantly affected by N-nitro-L-arginine methyl ester.
Conclusions—These results indicate that the modulation of oxygen consumption by both endogenous and exogenous NO is preserved in the failing human myocardium and that the inhibition of kinin degradation plays an important role in the regulation of mitochondrial respiration.
Key Words: nitric oxide • oxygen • heart failure
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