1014-96 Dichloroacetate Impairs Energy Metabolism and Produces a Negative Inotropic Effect in Vascular Smooth Muscle

Abstract

Dichloroacetate (DCA) is a promising agent for treatment of congestive heart failure. By stimulation of pyruvate dehydrogenase, it facilitates the oxidation of glucose (and its metabolites pyruvate and lactate), decreases O 2 consumption, and optimizes efficiency of energy production by heart muscle. Its effect on the energy metabolism of vascular smooth muscle, however, is unknown. The effect of DCA on vascular smooth muscle was investigated in segments of porcine carotid arteries mounted in an organ bath and incubated in physiological salt solution (PSS) containing glucose and presence or absence of 1 mM DCA. DCA suppressed the production of lactic acid (0.03 ± 0.006 vs. 0.11 ± 0.01 μ mol/g/min.; p < 0.001, n = 8) and the level of pyruvate was reduced by 56% (p < 0.01) consistent with enhanced oxidation of glucose. However, O 2 consumption was unaffected. The levels of the Krebs cycle metabolites citrate and oxaloacetate were unaltered by DCA but aspartate and oxoglutarate were decreased by 66% (p < 0.005) and 30% (p < 0.02) respectively, suggesting increased Krebs cycle activity. Despite this, the level of ATP + Phosphocreatine was decreased by DCA (1.00 ± 0.09 vs. 1.40 ± 0.09 μ mol/g, p < 0.02, n = 8). DCA had no effect on high energy phosphate levels in control carotid arteries incubated in glucose-free PSS containing fatty acid (0.5 mM octanoate). Carotid arteries incubated in DCA and then stimulated to contract by K + -depolarization displayed a reduced rate of tension generation when compared with controls (p < 0.05, n = 17). It is concluded that, in contrast to cardiac muscle, DCA impairs energy metabolism and exerts a negative inotropic effect in vascular smooth muscle in vitro. The impairment in energy metabolism is related to altered activity of the Krebs cycle as a result of excessive oxidation of glucose. Whether this effect on glucose metabolism and contractility of vascular smooth muscle occurs in vivo requires further investigation. The effects of DCA on the peripheral vasculature may play a role in its beneficial effects in congestive heart failure.