REGULATION OF ATP SENSITIVE POTASSIUM CHANNEL OF ISOLATED GUINEA-PIG VENTRICULAR MYOCYTES BY SARCOLEMMAL MONOCARBOXYLATE TRANSPORT

Objective: The aim was to describe the effects of extracellular application of monocarboxylates (pyruvate, lactate, or acetate) on current through K(ATP) channels (i(K,ATP)) in isolated guinea pig ventricular myocytes. Methods: The i(K-ATP) was elicited during whole cell voltage clamping by application of metabolic poisons, 2,4 dinitrophenol (150 muM) or glucose free cyanide (1 mM) and could be blocked by glibenclamide (3 muM) Results: Extracellular application of monocarboxylates, pyruvate (0.1-10 MM), L-lactate (0.1-10 mM), and acetate (10 mM) led to a rapid inhibition of i(K,ATP) - an effect which was fully reversible upon washout. Substances without any effect on i(K,ATP) were (10 mM each) gluconate, citrate, glutamate, creatine, succinate, and glycine. The mechanism underlying the effects of monocarboxylates on i(K,ATP) was unlikely to be related to an increased ATP production, since D-lactate (10 mM) essentially had the same effect on i(K,ATP) as the L-isomer of lactate. Furthermore, with intracellular dialysis of alpha-cyano-4-hydroxycinnamate (0.1-0.5 mM), which inhibits pyruvate uptake into mitochondria, extracellular pyruvate exerted the same inhibitory effect on i(K,ATP). High concentrations of extracellular alpha-cyano-4-hydroxycinnamate (4 mM), which blocks the sarcolemmal monocarboxylate carrier, prevented the effects on i(K,ATP) by pyruvate, L-lactate, D-lactate, and acetate. Furthermore, intracellular dialysis with D-lactate (10 mM) led to a more rapid onset of i(K,ATP) when activated by ATP free dialysis. Activity of isolated K(ATP) channels, measured in isolated membrane patches in the inside out or outside out configuration, typically had a single channel conductance of around 80 pS and was blocked by glibenclamide (3-9 muM). No significant effect of pyruvate was observed in either patch configuration. Conclusions: In cardiac tissue there may be some modulatory role involving monocarboxylate transport on K(ATP) channel activity, the nature of which is unclear at present but which may involve cytosolic pH changes. Physiological and pathophysiological implications of these findings are discussed.