Further studies on the mechanism by which chlorpropamide alters the action of vasopressin.
The injection of chlorpropamide into Brattleboro homozygous rats (di/di) has previously been shown to result in enhanced activation of renal medullary adenylate cyclase activity and increased renal medullary content of cAMP in response to 1-desamino-8-D-arginine vasopressin (dDAVP). In contrast, in vivo chlorpropamide did not alter GTP, guanylylimidodiphosphate, or fluoride-stimulated adenylate cyclase activities in these renal membranes. We have now found that the effect of in vivo chlorpropamide in enhancing dDVAP-stimulated adenylate cyclase activity involves lowering the Km for ATP. We have also found that dDAVP increases urinary prostaglandin E2 (PGE2) excretion, and treatment with chlorpropamide causes an even greater PGE2 response to dDAVP. In contrast, in vivo chlorpropamide treatment did not increase vascular responses to arginine vasopressin (AVP) in the perfused kidney preparation and, in fact, inhibited the AVP-induced decrease in the glomerular filtration rate. Chlorpropamide, therefore, enhances the renal responses to dDAVP in terms of the cAMP and PG systems, while not increasing responses to postreceptor stimuli of the adenylate cyclase system or vascular responses to AVP. These observations support the concept that in vivo chlorpropamide acts at the receptor of the vasopressin-sensitive part of the tubule to augment responsiveness to vasopressin. In addition, in vivo chlorpropamide may inhibit certain vascular responses to AVP.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002747:Chlorpropamide / Q000494:pharmacology*; D015232:Dinoprostone; D004347:Drug Interactions; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007679:Kidney Medulla / Q000187:drug effects / Q000201:enzymology; D011458:Prostaglandins E / Q000652:urine; D051381:Rats; D011910:Rats, Brattleboro; D014655:Vascular Resistance / Q000187:drug effects; D014667:Vasopressins / Q000494:pharmacology*
D011458:Prostaglandins E; D014667:Vasopressins; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D002747:Chlorpropamide