The effect of trimethyltin on acetylcholine release in the guinea-pig trachea |
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Authors: | Aas P Pagenhart A Eriksen S Kolderup J Fonnum F |
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Affiliation: | aNorwegian Defence Research Establishment, Division for Environmental Toxicology, P.O. Box 25, N-2007 Kjeller, Norway bUniversity of Oslo, Department of Biology, Oslo, Norway |
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Abstract: | 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 [3H]acetylcholine. The evoked release of endogenous acetylcholine and [3H]acetylcholine was released from a pool of acetylcholine being independent of extraneuronal Ca2+ in the presence, but not in the absence of trimethyltin. The effect of trimethyltin on the release was not inhibited by low Ca2+ (0 mM and 1.0 × 10−4 M) or by Ca2+ 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 -latrotoxin (1.0 × 10−8 M), a toxin from black widow spider venom inducing vesicle depletion, had no inhibitory effects on the release of [3H]acetylcholine evoked by trimethyltin (3.0 × 10−3 M). The release of [3H]acetylcholine was moreover enhanced by trimethyltin when the vesicular uptake of [3H]acetylcholine was inhibited by AH5183, probably as a result of a higher cytoplasmic concentration of [3H]acetylcholine. Trimethyltin also reduced the neuronal uptake of [3H]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 GH4 C1 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. |
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Keywords: | Acetylcholine Patch clamp Peripheral nervous system Trimethyltin Vesicle Ca2+ channel blocker |
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