AQA 39^*, a new bradycardic agent which blocks myocardial calcium (Ca) channels in a frequency- and voltage-dependent manner

Summary

AQA 39 is a new drug which resembles verapamil and D600 in chemical structure. However, under normal conditions (i.e., extracellular potassium of 5.4 mmol/l, 0.33 Hz stimulation rate, fully polarized healthy preparations), the effects of this agent on ventricular muscle bear remarkable differences to those of the classic Ca channel blocking agents under the same conditions, since AQA 39 does not affect either calcium-dependent electrical or mechanical activity. Therefore, the effects of this drug on rabbit ventricular muscle have been investigated in detail:

• 1. The action potential duration lengthened with concentration (10⁻⁶–10⁻⁴ mol/l) at stimulation rates of 0.33, 1, and 2 Hz. There was no change in the resting potential.

• 2. At 0.33 Hz, concentrations up to 10⁻⁴ mol/l had no effect on the action potential plateau amplitude or peak force of contraction. At 1 and 2 Hz depression was apparent at 5×10⁻⁶ mol/l and above.

• 3. The plateau amplitude of the slow action potential (20 mmol/l K⁺) was markedly depressed by AQA 39 (2×10⁻⁵ mol/l) at 0.33 Hz; peak force of contraction declined to about 30% control.

• 4. When voltage clamp steps were imposed from a holding potential of −50 mV, there was a large reduction in slow inward calcium current (I _si) and peak force of contraction at voltages between −40 and +40mV. The outward current was also depressed.

• 5. Changes in the reversal potential of I _si or in the voltage dependence of the activation kinetics were ruled out as explanation for the depression of I _si.

• 6. The block of Ca channels was dependent on the level of the diastolic potential. When I _si was depressed to about 30% control with 0.33 Hz stimulation from −50 mV, a 10 s rest at −50 mV was without effect but a 5 s rest at −85 mV restored I _si to the pre-drug amplitude.

• 7. It is concluded that AQA 39 at a critical concentration ought to allow normal rhythm but supress tachyarrhythmic episodes or early extrasystolic activity in the S-A node, the A-V node or depolarized myocardial foci without affecting electrical activity and contractility in other regions.