PROARRHYTHMIC EFFECTS OF DL-SOTALO AND D-SOTALOL ON THE BORDER ZONE BETWEEN NORMAL AND ISCHEMIC REGIONS OF ISOLATED VENTRICULAR MYOCARDIUM AND ANTIARRHYTHMIC EFFECTS ON REPERFUSION

Considering the Survival With ORal D-sotalol (SWORD) study results, in which mortality was higher in patients treated by the pure class III agent D-sotalol, we tested DL- and D-sotalol (5 and 10 mu M) in an in vitro model of ''border zone'' arrhythmias. Isolated guinea-pig ventri cular strips were partly exposed to normoxia (''Normal Zone,'' NZ) and partly to modified Tyrode's solution (''Ischemic Zone,'' IZ) for 15 o r 30 min (''ischemia''), followed by return to normoxia for 30 min ('' reperfusion''). Resting membrane potential, action potential (AP) ampl itude, and maximal upstroke velocity of AP were not significantly modi fied. Dr- And D-sotalol, 5 and 10 mu M, length ened AP duration 90% (A PD(90)) in NZ (p < 0.05), whereas these drugs were unable to prevent i schemia-induced APD shortening. By using the accelerated failure time Weibull's model, and a large number of reference experiments to contro l random variability of analyzed covariates, Dr-and D-sotalol increase d significantly the incidence of spontaneous arrhythmias during ischem ia (chi(2) = 24.79; p = 0.0367): 83 (5 mu M D- and DL-sotalol), 86, an d 62% (10 mu M D-and DL-sotalol, respectively) versus 32% of controls. During reperfusion, 10 mu M DL-sotalol prevented the occurrence of sp ontaneous arrhythmias (chi(2) = 46.74; p = 0.0001) similar to what see n with the beta-blocking agent propranolol (10 mu M). These data, prov iding evidence for proarrhythmic effects of DL- and D-sotalol on borde r-zone arrhythmias, concomitant with differential class III actions on NZ versus IZ, might be considered for understanding the SWORD study r esults.