Selective in vivo antagonism of pinacidil-induced hypotension by the guanidine U37883A in anesthetized rats.
The pyridylcyanoguanidine pinacidil exerts its hypotensive effect by opening ATP-sensitive potassium channels (K+ATP) in vascular smooth muscle. Direct glyburide-like antagonism of pinacidil-induced vasorelaxation by the guanidine U37883A (4-morpholinecarboximidine-N-1-adamantyl-N'- cyclohexylhydrochloride) has recently been demonstrated in isolated rabbit mesenteric artery. We herein report the first detailed in vivo cardiovascular interaction between U37883A and pinacidil in an anesthetized rat model. U37883A, administered from 0.1 to 3.0 mg/kg i.v. 10 min subsequent to pinacidil, immediately and dose-dependently reversed pinacidil's steady-state hypotensive effects by 29-100% (ED50 = 0.4 mg/kg), while reversal of pinacidil's tachycardiac effects from 10 to 79% was evident with 0.1-1.0 mg/kg i.v. U37883A (ED50 = 0.5 mg/kg). In contrast to these effects, pretreatment with 0.3-3.0 mg/kg i.v. U37883A only moderately inhibited the acute pinacidil-induced hypotension by 6-58%. Because U37883A's separate bradycardiac effects lowered basal heart rate, U37883A pretreatment precipitated a paradoxical 15-51% augmentation of sustained pinacidil-induced tachycardia, although absolute heart rates were below those seen with pinacidil alone. Qualitatively similar K+ATP blocking effects by U37883A were also observed in rats treated with the K+ATP openers (PCOs) cromakalim (BRL 34915), RPS 49365 and minoxidil. However, U37883A-treated rats remained responsive to the hypotensive action of both i.v. sodium nitroprusside and isoproterenol and buccal nifedipine. This study corroborates prior in vitro and in vivo findings and establishes that the guanidine U37883A is an effective and relatively selective blocker of PCO-induced vasodilation in the anesthetized rat. U37883A also appears more effective at closing basally and pinacidil-opened K+ATP than preventing K+ATP opening by pinacidil in vivo.
Smith
M P
MP
Upjohn Company, Kalamazoo, MI 49007.
Humphrey
S J
SJ
Jackson
W F
WF
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control*; D009025:Morpholines / Q000494:pharmacology*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013610:Tachycardia / Q000139:chemically induced / Q000517:prevention & control; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D004232:Diuretics; D006146:Guanidines; D009025:Morpholines; D015221:Potassium Channels; D014665:Vasodilator Agents; C082658:U 37883A; D020110:Pinacidil; D000218:Adamantane