Inhibition of glucose transport by cyclic GMP in cardiomyocytes.
Recent evidence points to a potential role of cyclic GMP (cGMP) in the control of cardiac glucose utilization. The present work examines whether the glucose 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 microM) caused a decrease in glucose transport in non-stimulated (basal) myocytes, as well as in cells stimulated with insulin or with the mitochondrial inhibitor oligomycin B by up to 40%. An inhibitory effect was also observed with another cGMP analogue (8-bromo-cGMP), and in cells stimulated by hydrogen peroxide or anoxia. In contrast, 8-p-CPT-cAMP (200 microM), or the beta-adrenergic agonist isoprenaline (which increases cAMP levels) did not depress glucose transport, and even potentiated the effect of insulin. Blockade of endogenous cGMP formation with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM) significantly increased basal and insulin-dependent glucose transport (by 25%), whereas addition of the guanylate cyclase activator 3-(5'-hydroxymethyl-2'furyl)-1-benzylindazol (YC-1, 30 microM) produced a depression of glucose transport (by 20%). Confocal laser scanning microscopic studies revealed that cGMP partially prevents the insulin-induced redistribution of the glucose transporter GLUT4 from intracellular stores to the cell surface. These observations suggest that the glucose transport system of cardiomyocytes represents a metabolic target of inhibition by cGMP, and that this regulation occurs at the level of the trafficking of glucose transporters.
Bergemann
C
C
Institute of Physiology, Medical Faculty, RWTH Aachen, Germany.
Löken
C
C
Becker
C
C
Graf
B
B
Hamidizadeh
M
M
Fischer
Y
Y
D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D015687:Cell Hypoxia / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism*; D004338:Drug Combinations; D005260:Female; D051275:Glucose Transporter Type 4; D006019:Glycolysis / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D018613:Microscopy, Confocal; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D009124:Muscle Proteins; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology
C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D004338:Drug Combinations; D051275:Glucose Transporter Type 4; D007191:Indazoles; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D009840:Oligomycins; D010069:Oxadiazoles; C495694:Slc2a4 protein, rat; D012402:Rotenone; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C048335:oligomycin B; D003847:Deoxyglucose; D006861:Hydrogen Peroxide; D006152:Cyclic GMP