Renal and vascular effects of chemically distinct ATP-sensitive K+ channel blockers in rats

Abstract

The ATP-sensitive K+ channel blocker U-37883A was given intravenously (i.v.) to rats to determine if pharmacologic diversity among ATP-sensitive K+ channels observed in vitro is also apparent in vivo. Vascular K+ channel blockade was quantified as inhibition of the decrease in blood pressure (BP) produced by a standard dose of the K+ channel opener pinacidil. Renal natriuretic effects were evaluated by an increase in urinary Na+ excretion. In both instances, effects of U-37883A, a guanidine, were compared with those of the sulfonylurea glyburide. In addition, the ability of these K+ channel blockers to lower plasma glucose levels was compared. U-37883A was nine times more potent than glyburide as a natriuretic and a comparable six times more potent than glyburide in blocking pinacidil, suggesting common features between ATP-sensitive K+ channels in vascular smooth muscle (VSM) and renal tubules. In contrast, a dose of U-37883A that blocked pinacidil and increased Na+ excretion had no effect on plasma glucose, whereas a dose of glyburide that was natriuretic and equally as effective against pinacidil as U-37883A decreased plasma glucose, suggesting that ATP-sensitive K+ channels in pancreatic beta cells and renal tubules have dissimilar binding sites and/or features. U-37883A appeared to be more renal/vascular selective, an observation entirely consistent with previous findings in vitro. Our results represent the first in vivo suggestion of structural differences among the channel and/or accessory proteins from this family of K(+)-selective channels.