Electromechanical effects of leukotriene D4 on ferret tracheal muscle and its muscarinic responsiveness

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Abstract
We investigated the possible electrophysiological processes by which leukotriene D4 (LTD4) affects airway smooth muscle and its responsiveness to acetylcholine (ACh). For study in vitro, preparations of ferret tracheal muscle (dissected free of overlying mucosal and submucosal layers) were used. These preparations were arranged so that force transducers and glass intracellular microelectrodes (having tip resistances of 35–60 megohm) could be used to measure isometric force generation and cell membrane potential (Em) simultaneously from muscle stimulated by LTD4. At rest, the muscle was electrically and mechanically quiescent and had an Em of −59±0.2 mV (mean±SEM). We found that ferret tracheal muscle cells were relatively sensitive to LTD4, and that both the resulting depolarization (beginning at 10−10 M LTD4) and force generation (produced by higher concentrations) progressed in a concentration-dependent manner. Depolarization by 10−9 M LTD4 elicited electrical oscillations. These oscillations were accompanied by phasic contractile activity at 5 × 10−9 M LTD4. Verapamil abolished these oscillations and diminished force substantially. We also found that ACh depolarized and contracted the muscle in a concentration-dependent manner. It caused electrical oscillations at ≥ 10−6 M. Diltiazem abolished these oscillations and markedly diminished force generation without affecting Em. Preexposure of airway muscle preparations for 20 min to a concentration (10−10 M) of LTD4 that, by itself, did not produce significant force, substantially augmented the voltage-tension relationship of the muscle upon ACh stimulation. We conclude that there is an electrical basis for the slow, prolonged force generation of airway muscle caused by LTD4, and that LTD4 potentiates the electromechanical responsiveness of the airway muscle to muscarinic stimulation.