Influence of ATP-sensitive potassium channel modulators on ischemia-induced fibrillation in isolated rat hearts.
We have confirmed the findings of Kantor and colleagues that ischemia-induced fibrillation in isolated Langendorff-perfused rat hearts can be prevented by glyburide, a blocker of ATP-dependent K channels. These data suggest that block of ATP-dependent K current [IK(ATP)] is a novel antiarrhythmic mechanism. This hypothesis was further tested by evaluating the effects of another sulfonylurea IK(ATP) blocker, tolbutamide (1 mM) and two agents known to activate these channels in cardiac tissue, BRL 34915 (10 microM) and pinacidil (30 microM). Similar to glyburide, tolbutamide was also effective in preventing fibrillation in this isolated rat heart model. The IK(ATP) activators enhanced the rate of tachycardia and shortened the time required for the hearts to develop fibrillation. Coadministration of glyburide with either IK(ATP) activator prevented their effects. It is concluded that activation of IK(ATP) during global ischemia contributes to the development of fibrillation in the perfused rat heart model.
Wolleben
C D
CD
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
Sanguinetti
M C
MC
Siegl
P K
PK
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001578:Benzopyrans / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000503:physiopathology*; D019806:Cromakalim; D005905:Glyburide / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014044:Tolbutamide / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D000959:Antihypertensive Agents; D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D020110:Pinacidil; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005905:Glyburide