The electrophysiological basis of the bradycardic action of AQA 39 on the sinoatrial node.

The electrophysiological effects of the bradycardic agent AQA 39 (5,6-dimethoxy-2-[3-[[ alpha-(3,4-dimethoxy) phenylethyl] methylamino] propyl] phthalimidine hydrochloride) on small preparations of the S-A node of the rabbit heart were investigated. The following results were obtained: 1. The decrease in the rate of the spontaneous preparation resulted from a lower rate of diastolic depolarization, a slower upstroke and a longer duration of the action potential. Concomitantly, overshoot and maximum diastolic potential were decreased. 2. The drug effect on rate strongly depended on the potential during diastole. AQA 39 acted stronger the more positive the maximum diastolic potential. 3. In voltage-clamp experiments, the membrane potential was held at -40 mV and transiently depolarized by square pulses to -10 mV. At a low pulsing rate (0.005 Hz), the main effect was a reduction of the time-dependent potassium current (Ik); the slow inward current (Isi) was only slightly reduced. However, when the pulsing rate was increased to 1 Hz, a clear reduction of Isi was observed. 4. When the block of Ca channels had reached a steady state during continuous pulsing in the presence of the drug, part of the block could be removed by rest periods, relief of block being dependent on the membrane potential during rest. At a fixed rest period of 45s, relief of block was nearly complete for potentials negative to -55 mV but negligible positive to -35mV. 5. AQA 39 shifted the dose-response curve to ionophoretic application of acetylcholine to higher concentrations, suggesting a competitive action of the drug with acetylcholine at the muscarinic receptor.