Molyvdas P A, James F W, Sperelakis N
Department of Physiology, College of Medicine, University of Cincinnati, OH 45267-0576.
Eur J Pharmacol. 1989 May 30;164(3):547-53. doi: 10.1016/0014-2999(89)90263-x.
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.
采用传统微电极技术，在豚鼠乳头肌（于37℃用含氧的台氏液灌流）上，研究了一种正在临床研究的新型抗哮喘药物氮卓斯汀对正常快动作电位（APs）和慢动作电位的作用。慢动作电位由10⁻⁷ M异丙肾上腺素、10⁻⁵ M组胺、二丁酰环磷腺苷（db - cAMP，3 mM）或10 mM四乙铵（TEA）诱发，同时存在25 mM细胞外钾离子（[K]o）使快钠离子通道失活。在10⁻⁵ M时，氮卓斯汀降低了慢动作电位的最大上升速率（+Vmax）和收缩力。在3×10⁻⁵ M时，氮卓斯汀进一步降低+Vmax和慢动作电位的幅度；在10⁻⁴ M时慢动作电位和收缩完全消失。药物洗脱后，自动节律性出现。在存在10⁻⁴ M氮卓斯汀的情况下，将细胞外钙浓度（[Ca]o）从1.8 mM增加到3.6 mM和5.4 mM，可使慢动作电位和收缩部分恢复。快动作电位也受到氮卓斯汀的抑制。在10⁻⁵ M和3×10⁻⁵ M时，氮卓斯汀降低了快动作电位的+Vmax和复极化50%时的动作电位时程（APD50）。在10⁻⁴ M氮卓斯汀作用30分钟后，观察到快动作电位完全阻断和收缩抑制。洗脱3 - 5小时后，兴奋性恢复；然而，+Vmax降低，APD90延长。结论是氮卓斯汀抑制慢钙通道和快钠通道。恢复缓慢表明该药物可能在细胞内蓄积，并对收缩产生持久的抑制作用。
