Therapeutic Research

Abstract

Electrophysiological effects of promethazine hydrochloride, an H1 histamine receptor antagonist, on spontaneous action potentials and membrane currents were studied using small preparations（0.2×0.2×0.1 mm）of rabbit sinoatrial（SA）node. Promethazine（3, 10μM）progressively decreased maximal diastolic potential, rate of diastolic depolarization and maximal rate of depolarization, and prolonged action potential duration and diastolic interval in a concentration−dependent manner. At 10μM, the spontaneous activity ceased in 3 of 6 preparations. In voltage clamp experiments using double microelectrode techniques, 10μM promethazine reduced L−type Ca2＋ current（ICa,L）obtained on step depolarization from −40 to 0mV by 19±4％, delayed rectifying K＋ current（IK）tail obtained on repolarization from ＋10 to −40mV by 24±6％, and hyperpolarization−activated inward current （Ih）at −80mV by 34±4％, respectively（n＝5, p＜0.05）. 10μM promethazine caused a marked use− or frequency−dependent block of ICa,L in a frequency−dependent manner. Steady−state inactivation curve for ICa,L was not altered by 10μM promethazine. Recovery of ICa,L from inactivation was retarded（time constant＝1985±319ms）at a holding potential of −40mV in the presence of 10μM promethazine（n＝4）. Steady−state activation curve for IK wasunchanged by 10μM promethazine. These results suggest that（1）promethazine exerts anegative chronotropic action by decreasing conductance of ICa,L, IK and Ih in rabbit SA node,and（2）recovery kinetics of promethazine from L−type Ca2＋ channel inactivation was slowand therefore the drug showed a marked use− or frequency−dependent block of ICa,L.