Electrophysiologic effects of ketanserin on canine Purkinje fibers, ventricular myocardium and the intact heart
Zaza, A.; Malfatto, G.; Rosen, M.R.
Journal of Pharmacology and Experimental Therapeutics 250(1): 397-405
1989
ISSN/ISBN: 0022-3565 PMID: 2746507 Document Number: 337776
We studied the actions of ketanserin (KT) on transmembrane action potentials (AP) of canine Purkinje fibers (PF) and ventricular muscle (VM) and on rhythm in vivo. PF AP duration (APD) was increased by KT (10-8 to 10-6 M) and shortened at 10-5 M. KT effect on APD was greater during stimulation at longer cycle lengths at KT induced early afterdepolarizations in two of six PF at [K+]0 = 2.7 mM. Maximum diastolic potential, AP amplitude and .ovrhdot.Vmax were not changed by KT. In VM, KT (10-8 to 10-6 M) prolonged APD; but 10-5 M KT did not shorten APD, reducing the difference in APD between VM and PF. KT had no effect on slow response .ovrhdot.Vmax or amplitude but prolonged APD. To analyze whether changes in Na plateau current or transient outward current contributed to KT effects on APD, we used tetrodotoxin (TTX) and 4-aminopyridine. TTX shortened APD and in its presence, KT (10-5 M) induced no further shortening. In contrast, the effect of KT persisted in the presence of 4-aminopyridine. In six anestetized, open chest dogs, KT prolonged the QT interval, but did not modify QRS duration and epicardial conduction time or induce arrhythmias. KT facilitated the onset of torsades de pointes during epicardial aconitine application. We conclude: 1) KT (.ltoreq. 10-6 M) has "Class III" antiarrhythmic properties and at higher concentrations decreases APD; 2) potentially arrhythmogenic effects of KT are EAD induction and altered dispersion of repolarization; 3) an action on TTX-sensitive plateau currents contributes to the effect of high doses of KT on repolarization and; 4) in vivo, KT prolongs the QT interval and, although not directly arrhythmogeic, can facilitate torsades de pointes.