© 1993 by European Society of Cardiology
Copyright © 1993, European Society of Cardiology
Tacrine inhibits ventricular fibrillation induced by ischaemia and reperfusion and widens QT interval in rat
Cardiovascular Research Laboratories, Department of Pharmacology, Division of Biomedical Sciences, King's College, University of London, Manresa Road, London SW3 6LX, United Kingdom: S A Rees, M J Curtis.
Correspondence to Dr Curtis.
Objective: Tacrine was used as a tool to examine whether block of inward rectifying potassium current (IK1) represents a mechanism for suppression of arrhythmias induced by ischaemia and reperfusion. Methods: Isolated rat hearts (n=10-l2 per group) were subjected to 30 min left regional ischaemia followed by reperfusion with and without tacrine. Rat heart was used to permit delayed rectifier (IK) block to be disregarded in interpretation of results (rat ventricle is deficient in functional IK). Results: The incidence of ischaemia-induced ventricular fibrillation was reduced from 70% to 42%, 17% (p<0.05), and 0% (p<0.05) in hearts perfused with 0, 0.1, 1.0, and 10.0 µM tacrine. Likewise, the incidence of reperfusion induced ventricular fibrillation was reduced from 100% to 90%, 75%, and 50% (p<0.05), respectively. Indirect evidence of repolarisation delay by tacrine was provided by QT widening; for example, 15 min after the onset of ischaemia, QT (at 100% repolarisation) was increased from 194(SEM 6) to 231(17), 235(13) (p<0.05), and 341(24) ms (p<0.05) by increasing concentrations of drug. QT interval measured in individual hearts during ischaemia correlated inversely with arrhythmia score (r2=0.392; p<0.001). Tacrine had no effect on RR interval, coronary flow, recovery of flow during reperfusion, or occluded zone size. Tacrine caused bradycardia (significant at the 1.0 and 10.0 µM concentrations). In additional hearts (n=12 per group), reversal of 10.0 µM tacrine-induced sinus bradycardia by left atrial pacing (5 Hz) significantly reduced tacrine induced QT widening (p<0.05), and increased the incidence of ventricular fibrillation from 0% to 42% (although significant antiarrhythmic and QT widening effects were still present); 10.0 (µM tacrine failed to reduce the incidence of reperfusion induced ventricular fibrillation in paced hearts (92% incidence v 100% in controls). Conclusions: The novel antiarrhythmic effects of tacrine, a drug with established blocking action on IK, IK1, and slow inward current, appear to result from QT widening in the rat (dependent partly on IK1 blockade in the ventricles and partly on drug induced sinus bradycardia).
Cardiovascular Research 1993;27:453-458
KEYWORDS tacrine; ventricular fibrillation; myocardial ischaemia; reperfusion, IK1, IK1
Since MJC is a member of the Editorial Board of Cardiovasculur Research, professor E Carmeliet was appointed as a Guest Editor to arrange the impartial review of this paper.
The work was funded in part by the British Pharmacological Society (S A R is supported by the A J Clark Award). We are grateful to H S Sidhu for technical assistance.
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