Inhibition of glucose transport by cyclic GMP in cardiomyocytes

Recent evidence points to a potential role of cyclic GMP (cGMP) in the cont rol of cardiac glucose utilization. The present work examines whether the g lucose transport system of cardiac myocyte is a site of this cGMP-dependent regulation. Treatment of isolated rat cardiomyocytes (for 10 min) with the membrane-permeant cGMP analogue 8-(4-chlorophenylthio)-cGMP (8-p-CPT-cGMP, 200 muM) caused a decrease in glucose transport in non-stimulated (basal) myocytes, as well as in cells stimulated with insulin or with the mitochond rial inhibitor oligomycin B by up to 40%. An inhibitory effect was also obs erved with another cGMP analogue (8-bromo-cGMP), and in cells stimulated by hydrogen peroxide or anoxia. In contrast, 8-p-CPT-cAMP (200 muM), or the b eta -adrenergic agonist isoprenaline (which increases cAMP levels) did not depress glucose transport, and even potentiated the effect of insulin. Bloc kade of endogenous cGMP formation with the guanylate cyclase inhibitor 1H-[ 1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 muM) significantly increas ed basal and in sulin-dependent glucose transport (by 25%), whereas additio n of the guanylate cyclase activator 3-(5 ' -hydroxymethyl-2 ' -furyl)-1-be nzylindazoI (YC-1, 30 muM) produced a depression of glucose transport (by 2 0%). Confocal laser scanning microscopic studies revealed that cGMP partial ly prevents the insulin-induced redistribution of the glucose transporter G LUT4 from intracellular stores to the cell surface. These observations sugg est that the glucose transport system of cardiomyocytes represents a metabo lic target of inhibition by cGMP, and that this regulation occurs at the le vel of the trafficking of,glucose transporters. (C) 2001 Elsevier Science I nc. All rights reserved.