Biphasic dose-response relationship observed with Bay k 8644 on atrioventricular nodal conduction inhibited by verapamil.

The effects of a calcium channel blocker, verapamil, on the atrioventricular (AV) node, are antagonized by calcium, intravenously infused, so long as plasma calcium concentration does not reach 5.0 or 5.5 mmol . 1−1, as previously shown. Beyond this, the antagonistic effects decrease progressively, so that there is a bellshaped relationship between dose (or concentration) and response. The purpose of the present experiments has been to investigate a possible similar dose-response curve with a calcium channel activator, Bay k 8644. The study was carried out in anaesthetized, atropinized dogs, with cardiac pacing. The His bundle potentials were recorded by endocavitary electrodes and the AV nodal effective refractory period was measured by the extrastimulus method. Verapamil impaired AV nodal conduction and additional infusion of Bay k 8644 at a rate of 1 μg · kg−1 · min−1 partly antagonized this effect. Increasing the infusion rate of Bay k 8644 to 5 μg kg−1 · min−1 did not further increase but reduced the antagonism. In other experiments where infusion of calcium had partly antagonized the effect of verapamil, Bay k 8644 infused after cessation of calcium infusion did not further antagonize the effect of verapamil which even became again increasingly marked. Consequently, in the AV node depressed by a calcium channel blocker, Bay k 8644 gives rise to a bell-shaped dose-response relationship of its verapamilantagonistic action and the reversal of this action by high doses of Bay k 8644 can be observed after both administration of either calcium or Bay k 8644 in moderate doses.