Azelastine inhibits agonist-induced electromechanical activity in canine tracheal muscle.

Abstract

We examined the effects of a new antiasthmatic drug, azelastine, on the electromechanical responses of airway smooth muscle to histamine, acetylcholine (ACh), and tetraethylammonium (TEA). Membrane potential and isometric force were simultaneously measured in isolated canine tracheal muscle using intracellular microelectrodes and a microforce transducer. Azelastine, at 1 microM, depressed the histamine-induced contractile force by more than 60 percent. The histamine-induced membrane depolarization was also inhibited, but to a much less extent, compared to the inhibition of contractile force. Similarly, contraction induced by ACh was inhibited by azelastine. In contrast to histamine, ACh elicited electrical oscillations concomitant with the membrane depolarization. Azelastine abolished these oscillations without affecting the depolarization. Azelastine inhibited the Ca2+-dependent slow action potentials (induced by 20 mM TEA) in a concentration-dependent manner; complete inhibition occurred at 30 microM. Such direct inhibitory effects of azelastine on agonist-induced airway muscle contraction may explain its ability to exert bronchodilatation in asthmatic patients. One of its mechanisms of action may involve inhibition of voltage-sensitive Ca2+ influx across the muscle cell membrane; however, additional actions intracellularly are possible.