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1 Physiology, New York Medical College, Valhalla, NY, USA
2 Medicine, Scuola Superiore Sant'Anna, Pisa, Italy
3 Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA
4 Medicine, Scuola Superiore Sant'Anna, Pisa, Italy; Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA
5 Physiology, New York Medical College, Valhalla, NY, USA; Medicine, Scuola Superiore Sant'Anna, Pisa, Italy
* To whom correspondence should be addressed. E-mail: fabio_recchia{at}nymc.edu.
Acute inhibition of NO synthase causes a reversible alteration in myocardial substrate metabolism. We tested the hypothesis that a prolonged NO synthase inhibition alters cardiac metabolic phenotype. Seven chronically instrumented dogs received 35 mg/kg/day of L-NAME orally for 10 days to inhibit NO synthesis and seven were used as controls. Cardiac free fatty acid (FFA), glucose and lactate oxidation were measured by infusing 3H-oleate, 14C-glucose and 13C-lactate. After 10 days of L-NAME administration, despite no differences in LV afterload, cardiac oxygen 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/100g, P<0.05 vs control) and lactate (21.6±5.6 vs 11.8±2.6 µmol/min/100g, P<0.05 vs control). When LV afterload was increased by angiotensin II infusion to stimulate myocardial metabolism, glucose oxidation was augmented further in the L-NAME group compared to control, while FFA oxidation decreased. Exogenous NO (diethylamine nonoate, 0.01 µmol/kg/min i.v.) could not reverse this metabolic alteration. Consistent with the accelerated rate of carbohydrate oxidation, total myocardial pyruvate dehydrogenase (PDH) activity and protein expression were, respectively, 38% and 34% higher in the L-NAME group compared to control. 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.
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