Evidence for prejunctional inhibitory muscarinic receptors on sympathetic nerves innervating guinea-pig trachealis muscle.

1 Relaxation responses induced by stimulation of the postganglionic sympathetic nerve trunk were studied in the isolated, fluid-filled, innervated tracheal tube preparation of the guinea-pig. 2 The thromboxane-mimetic U46619, prostaglandin F2 alpha and histamine each caused concentration-dependent increases in the intraluminal pressure (ILP) of the fluid-filled tracheal tube, reflecting contraction of the trachealis muscle. Sympathetic nerve stimulation in the presence of the spasmogens caused relaxations which increased with increasing ILP. Relaxant responses evoked in the presence of these three spasmogens were comparable at any given ILP. 3 Muscarinic agonists caused concentration-dependent increases in ILP, pilocarpine being more potent than acetylcholine. Sympathetic nerve-induced relaxations were reduced in the presence of pilocarpine and acetylcholine when compared to those obtained at the same ILP in the presence of U46619. This inhibitory effect of muscarinic agonists on sympathetic nerve-induced responses was concentration-dependent. 4 Exogenously applied noradrenaline opposed the contractile effect of U46619 and acetylcholine to a similar extent, indicating that a comparable degree of postjunctional functional antagonism exists between the sympathetic neurotransmitter noradrenaline and both spasmogens. 5 The selective M2 muscarinic antagonists, gallamine and methoctramine, altered neither the postjunctional contractile action of acetylcholine nor its inhibitory effect on sympathetic nerve-induced relaxations. In addition, the inhibitory effect of acetylcholine was not modified by concentrations of pirenzepine known to block M1 muscarinic receptors. 6 The postjunctional contractile action of acetylcholine and its inhibitory effect on sympathetic neuro-transmission were antagonized by atropine, by the M3 muscarinic antagonist hexahydrosiladiphenidol and by higher concentration of pirenzepine. 7. These results suggest that in the guinea-pig trachea, muscarinic cholinoreceptor agonists inhibit sympathetic neurotransmission via activation of muscarinic receptors located on the sympathetic nerve endings. These inhibitory prejunctional muscarinic heteroreceptors are of the M3 subtype.