Effects of New and Potent Methanesulfonanilide Class III Antiarrhythmic Agents on Myocardial Refractoriness and Contractility in Isolated Cardiac Muscle

Summary The effects of the new and potent methanesulfonanilide class III antiarrhythmic agents (E-4031, UK-66,914, and UK-68,798) on myocardial refractoriness and contractility were compared to those of d-sotalol in ferret isometrically contracting right ventricular papillary muscle preparations. During 1 Hz pacing at 37°C, the four class III agents elicited concentration-dependent increases in ventricular effective refractory period (ERP), with a relative order of potency of UK-68,798 > E-4031 > UK-66,914 > d-sotalol. EC25 values (effective concentration required to increase ERP 25% above baseline) were (in μM) UK-68,798. 0.018; E-4031, 0.058; UK-66,914, 0.501; and d-sotalol, 43.76. Maximal increases in ERP relative to baseline (% of baseline value) for the class III agents at 37°C (range of 44.5 ± 4.5 to 63.0 ± 3.1%) were greater than the maximal increases observed at 27°C (range of 15.0 ± 3.3 to 31.2 ± 4.8%), whereas the maximal absolute (ms) increases in ERP above baseline were comparable for the class III agents at both temperatures. Increases in ERP produced by the four class III agents at 37°C were significantly greater at a pacing frequency of 1 Hz (range of 70.0 ± 7.6 to 102.0 ± 2.3 ms) than at 3 Hz (range of 18.3 ± 4.4 to 31.0 ± 4.8 ms). During a temporary period of hypoxic perfusion at 37°C, increases in ERP produced by the four class III agents were reversed, such that “hypoxic” ERP values approximated pretreatment, baseline values. During 1 Hz pacing at 37°C, modest increases in developed tension (range of + 18 ± 8 to +27 ± 8% above baseline), with balanced increases in the rates of tension development and decline, were observed with the administrations of E-4031, UK-66,914, and UK-68,798. In contrast, d-sotalol produced minimal effects on myocardial contractility.