Unique natriuretic properties of the ATP-sensitive K(+)-channel blocker glyburide in conscious rats.
Small-conductance, ATP-sensitive K(+)-channels (KATP) localized in apical membranes of both thick ascending limb of the loop of Henle and cortical collecting duct cells may be involved in Na+ reabsorption and K+ secretion in the mammalian kidney. Possible pharmacologic tools to evaluate such an hypothesis may be the antidiabetic sulfonylureas which block K(+)-channels in pancreatic beta-cells. In saline-loaded conscious rats, glyburide (GLY) dose-dependently increased urinary Na+ excretion with little change in urinary K+ excretion after i.p. administration (10-100 mg/kg). In renal clearance studies, GLY at 25 mg/kg i.v. increased Na+ excretion 350% during the first hour post-treatment without affecting K+ excretion, glomerular filtration rate, mean arterial pressure 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 streptozotocin-induced diabetic rats was significantly greater than the change after drug vehicle in these animals. It is unlikely that the natriuresis produced by GLY is secondary to changes in plasma insulin and/or glucose because the doses used were far above GLY's insulin-releasing action (i.e., all natriuretic doses would have produced maximal insulin release) and GLY was natriuretic in streptozotocin-induced diabetic rats. It is possible that GLY interferes with reabsorption of Na+ by blocking KATP and thereby interrupting K+ recycling and Na(+)-2Cl(-)-K+ cotransport in the loop of Henle.
Cardiovascular Diseases Research, Upjohn Laboratories, Kalamazoo, Michigan.
M A
MA
Clark
S J
SJ
Humphrey
M P
MP
Smith
J H
JH
Ludens
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology
D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D000255:Adenosine Triphosphate; D012964:Sodium; D011188:Potassium; D005905:Glyburide