EFFECT OF AH5183 (VESAMICOL) ON CHOLINERGIC TRANSMISSION IN INTACT AIRWAY SMOOTH-MUSCLE

The effect of the vesicular acetylcholine (ACh) transport blocker trans-2-(4-phenyl-piperidino)-cyclohexanol (AH5183) was studied in bronchial smooth muscle during activation of the vagus nerve. AH5183 inhibited in a dose-dependent manner the Ca2+-sensitive electrically induced smooth muscle contractions in vitro with a half-inhibitory concentration (IC50) of 1.6 +/- 0.4-mu-M. The inhibition was complete within 68 +/- 1 min (n = 8) at approximately 20-mu-M AH5183 and was partly reversible after washing of the preparations. AH5183 (20-mu-M) reduced the level of endogenous ACh by 47.4 +/- 7.6% (n = 4) during this time period. The effect of AH5183 is most likely prejunctional, since the contractions induced post-junctionally by carbachol were not altered by AH5183. The irreversible anticholinesterase, soman, increased the tonus of airway smooth muscle as a result of accumulation of spontaneously released ACh from prejunctional leakage. AH5183 had no effect on this increase of muscle contraction. The present results show that the nerve-evoked release of ACh comes from an AH5183-sensitive pool, probably a vesicular pool, whereas leakage of ACh presumably comes from the cytoplasmic pool in airway smooth muscle.