INHIBITION OF MYOCARDIAL GLUCOSE-UPTAKE BY CGMP

Guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger of nit ric oxide (NO), regulates myocardial contractility. It is not known wh ether this effect is accompanied by a change in heart metabolism. We r eport here the effects of 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), a cGMP analog, on regulatory steps of glucose metabolism i n isolated working rat hearts perfused with glucose as the substrate. When glucose uptake was stimulated by increasing the workload, additio n of the cGMP analog totally suppressed this stimulation and accelerat ed net glycogen breakdown. 8-BrcGMP did not affect pyruvate dehydrogen ase activity but activated acetyl-CoA carboxylase, the enzyme that pro duces malonyl-CoA, an inhibitor of long-chain fatty acid oxidation. To test whether glucose metabolism could also be affected by altering th e intracellular concentration of cGMP, we perfused hearts with N-G-nit ro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, or w ith S-nitroso-N-acetylpenicillamine (SNAP), a NO donor. Perfusion with L-NAME decreased cGMP and increased glucose uptake by 30%, whereas pe rfusion with SNAP resulted in opposite effects. None of these conditio ns affected adenosine 3',5'-cyclic monophosphate concentration. Limita tion of glucose uptake by SNAP or 8-BrcGMP decreased heart work, and t his was reversed by adding alternative oxidizable substrates (pyruvate , beta-hydroxybutyrate) together with glucose. Therefore, increased NO production decreases myocardial glucose utilization and limits heart work. This effect is mediated by cGMP, which is thus endowed with both physiological and metabolic properties.