The blockade of $\dot V_{\max }$ of the atrioventricular action potential produced by the slow channel inhibitors verapamil and nifedipine

Summary

The effect of the slow channel inhibitors verapamil (2.2×10⁻⁷ mol/l and 2.2×10⁻⁶ mol/l) and nifedipine (5×10⁻⁸ mol/l) on atrioventricular action potential and automaticity was studied in small specimens prepared from the av-node of rabbits.

• 1. Nodal and NH-action potentials proved susceptible to isoprenaline and responded to 2.3×10⁻⁹ mol/l with a $\dot V_{\max }$ increase of 44.0±6.4% and 40.0±8.5%, respectively. $\dot V_{\max }$ and overshoot were linearly related to the logarithm of external Ca and Na concentration. The overshoot of N-cells changed by 18 mV and the overshoot of NH-cells by 16 mV per tenfold variation in the external Ca concentration. A similar strong deviation from the theoretical value derived from the Nernst equation appeared on varying the external Na concentration, yielding a slope factor of overshoot of 23 mV in N-cells and of 32 mV in NH-cells per tenfold concentration change.

• 2. Verapamil at the lower concentration abolished pacemaker activity of N-cells within 21.1±4.8 min and decreased $\dot V_{\max }$ to 38.9±5.8% of the initial control value, whilst overshoot declined by 13.3±2.0 mV. The same response was obtained in NH-cells. Higher concentrations led to cessation of automaticity within 7.3±1.3 min but the $\dot V_{\max }$ reduction observed just before pacemaker arrest did not differ from that produced by the lower verapamil concentration. Washout experiments of as long as 60 min did not remove the inhibitory drug action regardless of the concentration applied.

• 3. Stimulation experiments performed after the occurrence of pacemaker arrest indicated that verapamil induces both a resting-state and a use-dependent block. In the absence of major changes of threshold potential, the latter developed exponentially. The interstimulus interval strongly affected the use-dependent block in that a decrease both enhanced the strength and diminished the time constant of development, and vice versa. Removal of the use-dependent block needed 20–30 s. The strength of both types of block increased with increasing exposure to verapamil until a complete resting-state block abolished excitability of the atrioventricular cell.

• 4. Elevated Ca concentrations as tested up to 5 mmol/l restored pacemaker activity and increased $\dot V_{\max }$ but did not abolish the use-dependent block. In a train of spontaneously generated action potentials, $\dot V_{\max }$ declined from beat to beat until complete blockade occurred which initiated a resting period of several seconds.

• 5. Nifedipine caused a pacemaker arrest in N-cells within 12.5±3.0 min and a reduction of $\dot V_{\max }$ to 54.8±14.0%. The same response was obtained in NH-cells. Like verapamil, nifedipine is capable of blocking $\dot V_{\max }$ already under resting conditions but the inhibitory drug action becomes strongly enhanced by repetitive stimulation. Excess Ca (5 mmol/l) weakened the rate-independent block but did not prevent the appearence of the use-dependent block.