Altered cardiac metabolic phenotype after prolonged inhibition of NO synthesis in chronically instrumented dogs

Abstract

Acute inhibition of nitric oxide (NO) synthase causes a reversible alteration in myocardial substrate metabolism. We tested the hypothesis that prolonged NO synthase inhibition alters cardiac metabolic phenotype. Seven chronically instrumented dogs were treated with Nω-nitro-l-arginine methyl ester (l-NAME, 35 mg·kg−1·day−1po) for 10 days to inhibit NO synthesis, and seven were used as controls. Cardiac free fatty acid, glucose, and lactate oxidation were measured by infusion of [3H]oleate, [14C]glucose, and [13C]lactate, respectively. After 10 days of l-NAME administration, despite no differences in left ventricular afterload, cardiac O2consumption was significantly increased by 30%, consistent with a marked enhancement in baseline oxidation of glucose (6.9 ± 2.0 vs. 1.7 ± 0.5 μmol·min−1·100 g−1, P < 0.05 vs. control) and lactate (21.6 ± 5.6 vs. 11.8 ± 2.6 μmol·min−1·100 g−1, P < 0.05 vs. control). When left ventricular afterload was increased by ANG II infusion to stimulate myocardial metabolism, glucose oxidation was augmented further in the l-NAME than in the control group, whereas free fatty acid oxidation decreased. Exogenous NO (diethylamine nonoate, 0.01 μmol·kg−1·min−1iv) could not reverse this metabolic alteration. Consistent with the accelerated rate of carbohydrate oxidation, total myocardial pyruvate dehydrogenase activity and protein expression were higher (38 and 34%, respectively) in the l-NAME than in the control group. Also, protein expression of the constitutively active glucose transporter GLUT-1 was significantly elevated (46%) vs. control. We conclude that prolonged NO deficiency causes a profound alteration in cardiac metabolic phenotype, characterized by selective potentiation of carbohydrate oxidation, that cannot be reversed by a short-term infusion of exogenous NO. This phenomenon may constitute an adaptive mechanism to counterbalance cardiac mechanical inefficiency.