The natriuretic effect of glibenclamide: evidence for a non-luminal site of action.
Inhibition of sodium reabsorption in the loop of Henle (LOH) contributes to the natriuretic effect of systemically administered glibenclamide. Although it has been suggested that the underlying mechanism involves inhibition of low-conductance potassium channels in the apical membrane of the thick ascending limb, these channels are relatively insensitive to glibenclamide ( K(i) ~200 micro M). In the present study we used capillary electrophoresis techniques to determine plasma and tubular fluid concentrations of glibenclamide in anaesthetised, glibenclamide-infused rats during maximal natriuresis. The plasma glibenclamide concentration was 158+/-29 micro M, whereas that in the tubular fluid entering the LOH was below detectable limits (10 micro M). In additional experiments, rats were infused intravenously with either glibenclamide or vehicle alone, while the LOH was perfused with a standard, glibenclamide-free solution. Loop sodium reabsorption ( J(Na)) was significantly reduced in the rats receiving the drug (vehicle: J(Na) 1.65+/-0.05 nmol/min, n=23; glibenclamide: J(Na) 1.34+/-0.07 nmol/min, n=36; P<0.01). In a further group of rats, glibenclamide was introduced directly into the LOH at a concentration known to inhibit the low-conductance potassium channel in vitro (250 micro M). However, J(Na) was unaffected. These data confirm that systemic glibenclamide inhibits sodium reabsorption in the LOH but argue strongly that it does not act from the luminal site.
D000818:Animals; D019075:Electrophoresis, Capillary; D005919:Glomerular Filtration Rate; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007275:Injections, Intravenous; D008138:Loop of Henle / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism
D007004:Hypoglycemic Agents; D015221:Potassium Channels; D012964:Sodium; D011188:Potassium; D005905:Glyburide