Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators.
Marked prolongation of cardiac action potentials and of QT intervals has been associated with early afterdepolarizations and triggered activity in vitro and with ventricular tachycardia in vivo. Because the antihypertensive potassium channel activators pinacidil and cromakalim are known to accelerate repolarization in cardiac tissues, we performed in vitro and in vivo experiments to test the hypothesis that these agents would block the arrhythmogenic effects of delayed repolarization. Early afterdepolarizations and triggered activity were elicited in canine cardiac Purkinje fibers driven at cycle lengths of 4 seconds or more (K0, 2.7 mM) during superfusion with quinidine, cesium, or sematilide, a methylsulfonylamino parasubstituted analogue of procainamide with class III antiarrhythmic activity. The potassium channel activators invariably (17 of 17) abolished this form of abnormal automaticity. This effect was observed at low concentrations that did not alter action potential characteristics at shorter cycle lengths. Intravenous Cs+ (total dose, 4.5 mM/kg) was used to produce ventricular arrhythmias in anesthetized rabbits randomly pretreated in a double-blind fashion with either low-dose pinacidil (0.2 mg/kg) or vehicle. Pinacidil pretreatment resulted in significantly fewer total ventricular ectopic beats (168 +/- 157 versus 582 +/- 448, p less than 0.005) and episodes of ventricular tachycardia (four of nine versus nine of nine, p = 0.057). At this dose, pinacidil did not alter mean blood pressure before Cs+ and maximal hypertensive response after Cs+. In summary, the potassium channel activators pinacidil and cromakalim suppressed triggered activity related to prolonged repolarization at concentrations that did not affect action potential characteristics at normal rates in vitro; pinacidil blunted arrhythmias produced by cesium administration in vivo without lowering blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pediatrics, Vanderbilt University, Nashville, Tenn. 37232-6602.
F A
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Fish
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Prakash
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Roden
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001578:Benzopyrans / Q000494:pharmacology*; D005117:Cardiac Complexes, Premature / Q000503:physiopathology; D002586:Cesium / Q000494:pharmacology; D002712:Chlorides; D019806:Cromakalim; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004594:Electrophysiology; D006146:Guanidines / Q000494:pharmacology*; D009994:Osmolar Concentration; D020110:Pinacidil; D015221:Potassium Channels / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology; D011817:Rabbits; D013617:Tachycardia, Supraventricular / Q000503:physiopathology; D014665:Vasodilator Agents / Q000494:pharmacology
D001578:Benzopyrans; D002712:Chlorides; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D002586:Cesium; D020110:Pinacidil; C028019:cesium chloride; D011802:Quinidine