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

¹Department of Physiology, New York Medical College, Valhalla, New York; ²Scuola Superiore Sant'Anna, Settore di Medicina, Pisa, Italy; and ³Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio

Submitted 14 July 2005 ; accepted in final form 10 November 2005

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 N-nitro-L-arginine methyl ester (L-NAME, 35 mg·kg^–1·day^–1 po) 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 O₂ consumption 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^–1 iv) 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.

heart; metabolism; nitric oxide

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