Renal and vascular effects of chemically distinct ATP-sensitive K+ channel blockers in rats.
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.
Ludens
J H
JH
Upjohn Laboratories, Kalamazoo, Michigan 49001, USA.
Clark
M A
MA
Smith
M P
MP
Humphrey
S J
SJ
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine; D014665:Vasodilator Agents / Q000494:pharmacology
D001786:Blood Glucose; D006146:Guanidines; D009025:Morpholines; D015221:Potassium Channels; D014665:Vasodilator Agents; C082658:U 37883A; D020110:Pinacidil; D000255:Adenosine Triphosphate; D012964:Sodium; D000218:Adamantane