The effect of trimethyltin on acetylcholine release in the guinea-pig trachea.

The purpose of the present work was to characterise the effects of trimethyltin on the release of acetylcholine from parasympathetic nerves and its effect on the postjunctional cholinergic stimulation of a smooth muscle. The guinea-pig trachea has been used as a model. Prejunctionally, trimethyltin (3.0 × 10(-3) M) significantly enhanced in a reversible manner the high K(+) (75 mM) evoked release of endogenous acetylcholine and [(3)H]acetylcholine. The evoked release of endogenous acetylcholine and [(3)H]acetylcholine was released from a pool of acetylcholine being independent of extraneuronal Ca(2+) in the presence, but not in the absence of trimethyltin. The effect of trimethyltin on the release was not inhibited by low Ca(2+) (0 mM and 1.0 × 10(-4) M) or by Ca(2+) channel blockers (verapamil, 1.0 × 10(-4) M, flunarizine, 1.0 × 10(-4) M, ω-conotoxin GVIA, 2.0 × 10(-7) M and ω-agatoxin, 2.0 × 10(-7) M). The present results also demonstrate that trimethyltin induce emptying of a non-vesicular, probably a cytoplasmic storage pool of acetylcholine, since AH5183 (2.0 × 10(-5) M), an inhibitor of the translocation of acetylcholine into synaptic vesicles, and α-latrotoxin (1.0 × 10(-8) M), a toxin from black widow spider venom inducing vesicle depletion, had no inhibitory effects on the release of [(3)H]acetylcholine evoked by trimethyltin (3.0 × 10(-3) M). The release of [(3)H]acetylcholine was moreover enhanced by trimethyltin when the vesicular uptake of [(3)H]acetylcholine was inhibited by AH5183, probably as a result of a higher cytoplasmic concentration of [(3)H]acetylcholine. Trimethyltin also reduced the neuronal uptake of [(3)H]choline and this was probably due to a depolarising effect of trimethyltin on the cholinergic nerve terminals. A similar depolarisation induced by trimethyltin was observed during patch clamping of GH(4) C(1) neuronal cells. Postjunctionally, trimethyltin had no effect by itself or on the carbachol-induced smooth muscle contraction, indicating that trimethyltin did not have a general depolarising effect on smooth muscle cells or an effect on muscarinic receptors. Furthermore, the reduced electrical field-induced contraction and the subsequent increase in the basal smooth muscle tension that was observed by addition of trimethyltin was activity-dependent, and was most probably due to emptying of a nervous non-vesicular storage pool of acetylcholine, followed by rapid hydrolysis of acetylcholine by acetyl- and pseudocholinesterases.