UNIQUE NATRIURETIC PROPERTIES OF THE ATP-SENSITIVE K-CHANNEL BLOCKER GLYBURIDE IN CONSCIOUS RATS()

Small-conductance, ATP-sensitive K+-channels (K(ATP)) localized in api cal membranes of both thick ascending limb of the loop of Henle and co rtical collecting duct cells may be involved in Na+ reabsorption and K + secretion in the mammalian kidney. Possible pharmacologic tools to e valuate such an hypothesis may be the antidiabetic sulfonylureas which block K+-channels in pancreatic beta-cells. In saline-loaded consciou s rats, glyburide (GLY) dose-dependently increased urinary Na+ excreti on with little change in urinary K+ excretion after i.p. administratio n (10-100 mg/kg). In renal clearance studies, GLY at 25 mg/kg i.v. inc reased Na+ excretion 350% during the first hour post-treatment without affecting K+ excretion, glomerular filtration rate, mean arterial pre ssure or heart rate. GLY at 50 mg/kg was no more natriuretic than the 25 mg/kg dose, whereas 12.5 mg/kg of GLY increased Na+ excretion 200%. The change in Na+ excretion produced by 25 mg/kg of GLY in streptozot ocin-induced diabetic rats was significantly greater than the change a fter drug vehicle in these animals. It is unlikely that the natriuresi s produced by GLY is secondary to changes in plasma insulin and/or glu cose because the doses used were far above GLY's insulin-releasing act ion (i.e., all natriuretic doses would have produced maximal insulin r elease) and GLY was natriuretic in streptozotocin-induced diabetic rat s. It is possible that GLY interferes with reabsorption of Na+ by bloc king K(ATP) and thereby interrupting K+ recycling and Na+-2Cl--K+ cotr ansport in the loop of Henle.