Electrophysiologic actions of aprindine in rabbit atrioventricular node

Abstract

Aprindine hydrochloride is a potent antiarrhythmic agent against various atrial and ventricular tachyarrhythmias. To elucidate its pharmacological actions in the atrioventricular node, electrophysiologic experiments were conducted by applying microelectrode and voltage clamp methods to small preparations of the rabbit atrioventricular node. At a concentration 1 mumol/l, aprindine decreased the spontaneous firing frequency, maximal rate of depolarization, action potential amplitude, and take-off potential (P less than 0.05, n = 7). The spontaneous and rate-controlled action potential durations at 50 and 100% repolarization were prolonged by aprindine. Voltage-clamp experiments using the double microelectrode method revealed that aprindine blocked the slow inward current (Isi) in a voltage-dependent manner with a dissociation constant of 10 mumol/l and Hill coefficient of 0.8. The steady-state inactivation curve for Isi was shifted toward more negative potentials by 2.5 +/- 0.9 mV (P less than 0.05, n = 5) without a significant change in the slope factor. This finding suggests that aprindine has a higher affinity for inactivated slow inward (or Ca2+) channels than for resting channels. Aprindine caused use-dependent block of Isi, a result consistent with the drug's slow dissociation from inactivated Ca2+ channels. The delayed rectifying K+ current (IK) tail obtained on repolarization from +10 mV to -60 mV was significantly decreased from 15.4 +/- 2.4 to 6.8 +/- 1.4 nA (P less than 0.01, n = 6) and the deactivation time constant significantly increased by 20.7% (P less than 0.01, n = 6). The steady-state activation curve for IK was shifted in the hyperpolarized direction by 6.9 +/- 2.9 mV, suggesting a potent voltage-dependent block of this current by aprindine. The hyperpolarization-activated inward current (Ih) was decreased from 14.4 +/- 5.4 to 12.0 +/- 5.5 nA (P less than 0.05, n = 5). The transient outward and inward currents induced by 1 mumol/l acetylstrophanthidin were almost completely suppressed after the addition of 1 mumol/l aprindine. These results suggest that aprindine exerts a negative chronotropic action both by slowing deactivation of IK and by reducing Isi and Ih, and delays atrioventricular nodal conduction by reducing Isi and IK. These blocking actions of aprindine together with its inhibition of the transient outward and inward currents may explain its antiarrhythmic effects on the atrioventricular node.