COMBINED POTASSIUM AND CALCIUM-CHANNEL ANTAGONISTIC ACTIVITIES AS A BASIS FOR NEUTRAL FREQUENCY-DEPENDENT INCREASE IN ACTION-POTENTIAL DURATION - COMPARISON BETWEEN BRL-32872 AND AZIMILIDE

Objective: The effects of BRL-32872, azimilide and a selective blocker of the delayed rectifier potassium current, E-4031, were measured at two different basic cycle lengths (BCL), 300 and 1000 ms. Calcium chan nel antagonists of sarcolemmal (verapamil and nitrendipine) and sarcop lasmic reticulum (ryanodine) membranes were used to investigate whethe r the inhibition of the calcium current or the calcium release from th e sarcoplasmic reticulum could alter the reverse-rate dependence of E- 4031 on action potential duration (APD). Methods: Guinea pig isolated papillary muscles were superfused with a Tyrode solution maintained at 37 degrees C and stimulated at a BCL of 300 or 1000 ms. The standard microelectrode technique was used to record action potential parameter s and to study the effects of azimilide, BRL-32872 and E-4031. E-4031 was superfused at increasing concentrations (0.01, 0.03, 0.1 and 0.3 m u M) in the absence or in the presence of verapamil (0.3 mu M), nitren dipine (0.03 mu M) or ryanodine (0.1 mu M) Results: BRL-32872 and azim ilide induced a self-limited concentration-dependent increase in APD. The effect of BRL-32872 was not dependent on the stimulation frequency whereas the effect of azimilide was significantly reduced at the shor ter BCL. E-4031 induced a concentration-dependent increase in APD at b oth stimulation BCL. The increase in APD was significantly more pronou nced in fibres stimulated at a BCL of 1000 ms than in fibres stimulate d at a BCL of 300 ms, characterising the reverse-frequency dependent e ffect of class III antiarrhythmic agents. The reverse-frequency depend ence in action potential prolongation induced by E-4031 was significan tly reduced in the presence of a low concentration of verapamil (0.3 m u M), nitrendipine (0.03 mu M), or ryanodine (0.1 mu M). Conclusion: T he results show that BRL-32872, in contrast to azimilide, does not ind uce the reverse-rate dependency of action potential prolongation typic ally produced by class III antiarrhythmic agents such as E-4031. Our r esults also show that reverse-rate dependency induced by E-4031 can be reduced by the simultaneous administration of a low concentration of a calcium channel antagonist or an inhibitor of the release of calcium from the sarcoplasmic reticulum. It is thus suggested that compounds with a suitable balance of potassium and calcium antagonistic activiti es may have less adverse effects than purely selective potassium chann el blockers. (C) 1998 Elsevier Science B.V.