REDUCED NITRIC-OXIDE PRODUCTION AND ALTERED MYOCARDIAL-METABOLISM DURING THE DECOMPENSATION OF PACING-INDUCED HEART-FAILURE IN THE CONSCIOUS DOG

The aim of the present study was to determine whether cardiac nitric o xide (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 p aced until left ventricular end-diastolic pressure reached 25 mm Hg an d clinical signs of severe failure were evident. Every week, hemodynam ic measurements were recorded and blood samples were withdrawn from th e aorta and the coronary sinus for measurement of NO metabolites, O-2 content, free fatty acids (FFAs), and lactate and glucose concentratio ns. Cardiac production of NO metabolites or consumption of O-2 or util ization of substrates was calculated as coronary sinus-arterial differ ence times coronary flow. In end-stage failure, occurring at 29 +/- 1. 6 days, left ventricular end-diastolic pressure was 25 +/- 1 mm Hg, le ft ventricular systolic pressure was 92 +/- 3 mm Hg, mean arterial pre ssure was 75 +/- 2.5 mm Hg, and dP/dt(max) was 1219 +/- 73 mm Hg/s (al l P<0.05). These changes in hemodynamics were associated with a fall o f cardiac NO metabolite production from 0.37 +/- 0.16 to -0.28 +/- 0.1 3 nmol/beat (P<0.05). O-2 consumption and lactate uptake did not chang e significantly from control, while FFA uptake decreased from 0.16 +/- 0.03 to 0.05 +/- 0.01 mu Eq/beat and glucose uptake increased from -2 .3 +/- 7.0 to 41+10 mu g/beat (P<0.05). The cardiac respiratory quotie nt also increased significantly by 28%. In 14 normal dogs the same mea surements were performed at control and 1 hour after we injected 30 mg /kg of nitro-L-arginine, a competitive inhibitor of NO synthase. O-2 c onsumption 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 fr om 0.1 +/- 0.01 to 0.06 +/- 0.01 mu Eq/beat, lactate uptake increased from 0.15 +/- 0.04 to 0.31 +/- 0.03 mu mol/beat, glucose uptake increa sed from 8.2 +/- 5.0 to 35.4 +/- 9.5 mu g/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 th ere are shifts in substrate utilization. This switch in myocardial sub strate utilization also occurs after acute pharmacological blockade of NO production in normal dogs.