Comparative effects of the potassium channel openers cromakalim and pinacidil and the cromakalim analog U-89232 on isolated vascular and cardiac tissue.
ATP-sensitive potassium (K+ATP) channel openers such as cromakalim and pinacidil exhibit both potent vasodilatory and anti-ischemic properties. U-89232, a cyanoguanidine analog of cromakalim, has recently been found to exhibit myocardial protection during ischemia without altering in vivo hemodynamics. We examined the effects of U-89232, cromakalim and pinacidil in isolated vascular and cardiac tissue and tested whether glyburide, a KATP channel blocker, could antagonize their effects. All three compounds produced concentration-dependent relaxation in isolated vascular segments, with cromakalim being approximately 100-fold more potent than either pinacidil or U-89232. Glyburide completely antagonized the effects of pinacidil but merely blunted the effects of cromakalim and U-89232. In an isolated rabbit cardiac tissue preparation, U-89232 had little effect on maximum tension in cardiac muscle, whereas cromakalim and pinacidil significantly decreased maximum developed tension in a concentration-dependent manner. Glyburide effectively antagonized the effects of cromakalim and pinacidil in cardiac tissue. These data suggest that U-89232, although chemically related to cromakalim, possesses activity which is not common to known potassium channel openers.
Upjohn Laboratories, Upjohn Company, Kalamazoo, Mich. 49001.
N R
NR
Norman
C F
CF
Toombs
S A
SA
Khan
L V
LV
Buchanan
M G
MG
Cimini
J K
JK
Gibson
K D
KD
Meisheri
R J
RJ
Shebuski
D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; C078774:U 89232; D020110:Pinacidil; D005905:Glyburide