ATTENUATION BY CREATINE OF MYOCARDIAL METABOLIC STRESS IN BRATTLEBORORATS CAUSED BY CHRONIC INHIBITION OF NITRIC-OXIDE SYNTHASE

1 The present experiment was undertaken to investigate: (a) the effect of nitric oxide synthase (NOS) inhibition, mediated by oral supplemen tation of the NOS inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME ), on measures of myocardial energy metabolism and function; (b) the e ffect of oral creatine supplementation on these variables, in the abse nce and presence of L-NAME. 2 In one series of experiments, 4 weeks or al administration of L-NAME (0.05 mg ml(-1) day(-1) in the drinking wa ter) to Brattleboro rats caused significant reductions in myocardial A TP, creatine, and total creatine concentrations and an accumulation of tissue lactate when compared with control animals. Administration of creatine (0.63 mg ml(-1) day(-1) in the drinking water) for 4 weeks el evated myocardial creatine and total creatine concentrations and reduc ed lactate accumulation, but did not significantly affect ATP or phosp hocreatine (PCr). Concurrent treatment with creatine and L-NAME preven ted the reduction in creatine and total creatine concentrations, and s ignificantly attenuated the accumulation of lactate and the reduction in ATP seen with L-NAME alone. 3 In a second series of experiments, 4 weeks treatment with L-NAME and creatine plus L-NAME increased mean ar terial blood pressure in conscious Brattleboro rats. Hearts isolated f rom these animals showed decreased coronary flow and left ventricular developed pressure (LVDP), and total mechanical performance. Treatment with creatine alone had no measurable effect on either mean arterial blood pressure or coronary flow in isolated hearts. However, there was an increase in LVDP, but not in total mechanical performance, because there was a bradycardia. 4 These results indicate that creatine suppl ementation can attenuate the metabolic stress associated with L-NAME a dministration and that this effect occurs as a consequence of the acti on of creatine on myocardial energy metabolism.