The effects of azelastine, a new anti-asthmatic drug under clinical investigation, were studied on both normal fast action potentials (APs) and slow APs using conventional microelectrode techniques in guinea pig papillary muscles (superfused with oxygenated Tyrode solution at 37 degrees C). Slow APs were induced by either 10(-7) M isoproterenol, 10(-5) M histamine, db-cAMP (3 mM) or 10 mM TEA, in the presence of 25 mM [K]o to voltage inactive the fast Na+ channels. At 10(-5) M, azelastine depressed the maximum rate of rise (+Vmax) of the slow APs and the force of contraction. At 3 X 10(-5) M, azelastine further reduced +Vmax and the amplitude of the slow APs; complete abolishing of slow APs and contractions occurred at 10(-4) M. Upon washout of the drug, automaticity appeared. In the presence of 10(-4) M azelastine, increasing the [Ca]o concentration from 1.8 to 3.6 and 5.4 mM caused partial recovery of the slow APs and contractions. The fast APs were also depressed by azelastine. At 10(-5) and 3 X 10(-5) M, azelastine reduced +Vmax and the AP duration at 50% repolarization (APD50) of the fast APs. Complete block of the fast APs and suppression of contractions were observed after 30 min at 10(-4) M azelastine. After 3-5 h of washout, excitability recovered; however, +Vmax was depressed and APD90 was prolonged. It is concluded that azelastine inhibits the slow Ca2+ channels and the fast Na+ channels. The slow recovery suggests that the drug may accumulate inside the cells, and exert a prolonged inhibitory effect on contraction.