SELECTIVE IN-VIVO ANTAGONISM OF PINACIDIL-INDUCED HYPOTENSION BY THE GUANIDINE U37883A IN ANESTHETIZED RATS

The pyridylcyanoguanidine pinacidil exerts its hypotensive effect by o pening ATP-sensitive potassium channels (K-ATP(+)) in vascular smooth muscle. Direct glyburide-like antagonism of pinacidil-induced vasorela xation by the guanidine U37883A (4-morpholinecarboximidine-N-1-adamant yl-N'- cyclohexylhydrochloride) has recently been demonstrated in isol ated rabbit mesenteric artery. We herein report the first detailed in vivo cardiovascular interaction between U37883A and pinacidil in an an esthetized rat model. U37883A, administered from 0.1 to 3.0 mg/kg i.v. 10 min subsequent to pinacidil, immediately and dose-dependently reve rsed pinacidil's steady-state hypotensive effects by 29-100% (ED(50) = 0.4 mg/kg), while reversal of pinacidil's tachycardiac effects from 1 0 to 79% was evident with 0.1-1.0 mg/kg i.v. U37883A (ED(50) = 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 hypote nsion by 6-58%. Because U37883A's separate bradycardiac effects lowere d 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. Qual itatively similar K-ATP(+) blocking effects by U37883A were also obser ved in rats treated with the K-ATP(+) openers (PCOs) cromakalim (BRL 3 4915), RPS 49365 and minoxidil. However, U37883A-treated rats remained responsive to the hypotensive action of both i.v. sodium nitroprussid e and isoproterenol and buccal nifedipine. This study corroborates pri or in vitro and in vivo findings and establishes that the guanidine U3 7883A is an effective and relatively selective blocker of PCO-induced vasodilation in the anesthetized rat. U37883A also appears more effect ive at closing basally and pinacidil-opened K-ATP(+) than preventing K -ATP(+) opening by pinacidil in vivo.