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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.

1 Interactions between pulmonary cholinergic and noradrenergic nerves were studied in the innervated tracheal tube preparation isolated from guinea-pigs anaesthetized with urethane. Relaxations of the trachealis smooth muscle in response to postganglionic stimulation of the sympathetic nerve were recorded as decreases in the intraluminal pressure of the tracheal tube after the pressure had been raised with the stable thromboxane-mimetic, U46619. In contrast, contractions following preganglionic stimulation of the vagal nerve trunk were recorded as increases in intraluminal pressure.2 In approximately half of the preparations studied, concurrent stimulation of the vagal nerve trunk inhibited relaxation responses elicited by stimulation of the sympathetic nerves. The vagi were stimulated at parameters which caused no change in intraluminal pressure, excluding the involvement of postjunctional mechanisms. 3 The effect of simultaneous stimulation of the sympathetic nerve trunk was studied on contractile responses evoked by preganglionic stimulation of the vagus nerve. In 80% of the preparations tested the vagal responses were inhibited. This inhibitory effect of sympathetic nerve stimulation was antagonized by propranolol. 4 The potassium channel agonist, cromakalim, endothelins 1 and 3 and the neuropeptides, vasoactive intestinal peptide, neurokinin A and substance P, did not significantly modulate sympathetic nerveinduced relaxations. 5 The anticholinesterase drug, physostigmine, induced a concentration-dependent increase in the intraluminal pressure of the tracheal tube and potentiated the postjunctional action of exogenously applied acetylcholine to contract the guinea-pig trachealis muscle. In the presence of higher concentrations of physostigmine both vagally-induced contractions and sympathetic nerve-induced relaxations were reduced. Atropine blocked both the inhibitory effect of physostigmine on sympathetic relaxations and its postjunctional contractile action on the trachealis smooth muscle. 6 It is concluded that, in the guinea-pig trachea, acetylcholine released endogenously from pulmonary parasympathetic nerves, either by anticholinesterase drugs or in response to nerve stimulation, can inhibit transmission in the adjacent sympathetic nerves via activation of prejunctional muscarinic heteroreceptors, probably of the M3 subtype.

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