© 1998 American Heart Association, Inc.
Original Contributions |
Reduced Nitric Oxide Production and Altered Myocardial Metabolism During the Decompensation of Pacing-Induced Heart Failure in the Conscious Dog
From the Department of Physiology, New York Medical College, Valhalla.
Correspondence to Thomas Hintze, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas_Hintze{at}nymc.edu
Abstract—The aim of the present study was to determine whether cardiac nitric oxide (NO) production changes during the progression of pacing-induced heart failure and whether this occurs in association with alterations in myocardial metabolism. Dogs (n=8) were instrumented and the heart paced until left ventricular end-diastolic pressure reached 25 mm Hg and clinical signs of severe failure were evident. Every week, hemodynamic measurements were recorded and blood samples were withdrawn from the aorta and the coronary sinus for measurement of NO metabolites, O2 content, free fatty acids (FFAs), and lactate and glucose concentrations. Cardiac production of NO metabolites or consumption of O2 or utilization of substrates was calculated as coronary sinus-arterial difference times coronary flow. In end-stage failure, occurring at 29±1.6 days, left ventricular end-diastolic pressure was 25±1 mm Hg, left ventricular systolic pressure was 92±3 mm Hg, mean arterial pressure was 75±2.5 mm Hg, and dP/dtmax was 1219±73 mm Hg/s (all P<0.05). These changes in hemodynamics were associated with a fall of cardiac NO metabolite production from 0.37±0.16 to -0.28±0.13 nmol/beat (P<0.05). O2 consumption and lactate uptake did not change significantly from control, while FFA uptake decreased from 0.16±0.03 to 0.05±0.01 µEq/beat and glucose uptake increased from -2.3±7.0 to 41±10 µg/beat (P<0.05). The cardiac respiratory quotient also increased significantly by 28%. In 14 normal dogs the same measurements were performed at control and 1 hour after we injected 30 mg/kg of nitro-L-arginine, a competitive inhibitor of NO synthase. O2 consumption increased from 0.05±0.002 mL/beat at control to 0.071±0.003 mL/beat after nitro-L-arginine, while FFA uptake decreased from 0.1±0.01 to 0.06±0.01 µEq/beat, lactate uptake increased from 0.15±0.04 to 0.31±0.03 µmol/beat, glucose uptake increased from 8.2±5.0 to 35.4±9.5 µg/beat, and RQ increased by 23% (all P<0.05). Our results indicate that basal cardiac production of NO falls below normal levels during cardiac decompensation and that there are shifts in substrate utilization. This switch in myocardial substrate utilization also occurs after acute pharmacological blockade of NO production in normal dogs.
Key Words: MVO2 • lactate • free fatty acid • glucose • respiratory quotient
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