RATE-DEPENDENT EFFECTS OF THE CLASS-III ANTIARRHYTHMIC DRUG ALMOKALANT ON REFRACTORINESS IN THE PIG

The electrophysiologic effects of intravenously administered almokalan t, a new class III antiarrhythmic drug, in 7 isoflurane-anesthetized p igs after low and high dose were investigated. Low-dose almokalant inc luded bolus infusion of 0.05 mu mol/kg/min for 5 min followed by a con tinuous infusion of 0.0025 mu mol/kg/min for 40 min. Thereafter, a hig h dose of 0.2 mu mol/kg/min for 5 min and 0.01 mu mol/kg/min for 40 mi n was given. PR, QRS, AH, and HV intervals did not change during almok alant administration. The QT interval increased dose dependently from 337 +/- 17 to 442 +/- 20 ms at high dose (p < 0.05). Atrial refractory periods (AERP) were prolonged dose dependently at a 500-ms pacing cyc le length from 178 +/- 15 at baseline to 227 +/- 27 and 253 +/- 23 ms during low- and high-dose almokalant infusion, respectively. For pacin g cycle lengths of 400 and 300 ms, these values were 180 +/- 11, 207 /- 25, and 259 +/- 34 and 157 +/- 12, 193 +/- 21, and 234 +/- 28 ms, r espectively. At a pacing cycle length of 500 ms, mean ventricular effe ctive refractory period (VERP) was 270 +/- 25 ms as compared with 306 +/- 24 and 337 +/- 17 during low and high dose, respectively. A simila r pattern of VERP changes during both low- and high-dose infusion was noted at the shorter pacing cycle lengths, with an increase from 240 /- 23 to 274 +/- 22 and 279 +/- 24 ms during a 400-ms cycle length and from 210 +/- 17 to 235 +/- 19 and 234 +/- 21 ms during a 300-ms cycle length. The ratio of the VERP and ventricular monophasic action poten tial duration (VAPD) did not change significantly. The Wenckebach cycl e length increased by 36 +/- 36 and 83 +/- 37 ms with low- and high-do se almokalant infusion, respectively. The percent increase of AERP at pacing cycle lengths of 500, 400, and 300 ms during high-dose almokala nt was 42, 44, and 49%, respectively; these increases for VERP were 25 , 16, and 11%, respectively. In conclusion, prolongation of refractori ness by almokalant was more pronounced at the atrial than the ventricu lar level. Prolongation of refractoriness was maintained at short paci ng cycle lengths especially in the atrium, indicating absence of rever se-use dependence of almokalant in the porcine heart. The marked atria l effects, paralleled by atrioventricular conduction slowing, and the absence of reverse use-dependence all contribute to the feasibility of use of almokalant, in particular in the treatment of supraventricular tachyarrhythmias.