A probable mechanism for tolbutamide mediated activation of glycogen phosphorylase in the isolated rat heart.
Previous studies have shown that 0.6 mM tolbutamide stimulates the rate of glycogenolysis and transiently increases % phosphorylase a activity in the isolated rat heart. Since tolbutamide has been reported to activate adenylate cyclase, one possible mechanism for the conversion of phosphorylase b to the a form is through a cAMP mediated process. However, we failed to detect any drug-induced changes in tissue cAMP content of rat and rabbit hearts or in basal, Gpp(NH)p stimulated and isoproterenol-stimulated adenylate cyclase activity of sarcolemma prepared from rat, rabbit or dog ventricles. Since tolbutamide can alter calcium transport across cell membranes, we investigated the possibility that the drug's effects on phosphorylase were linked to an elevation in calcium concentration. It was found that tolbutamide was not able to activate phosphorylase when the calcium channel blocker verapamil was present in the perfusate. In addition, the sulfonylurea increased binding of [3H]-verapamil to isolated sarcolemma suggesting that tolbutamide is able to unmask previously inactive calcium channels and thereby stimulate calcium movement into the cell.
D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000032:analysis; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D006005:Phosphorylases / Q000032:analysis*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014044:Tolbutamide / Q000494:pharmacology*
D007473:Ion Channels; D014044:Tolbutamide; D000242:Cyclic AMP; D006005:Phosphorylases; D000262:Adenylyl Cyclases; D002118:Calcium