Pendry, Yvonne Dawn; (1990) Pharmacological classification of muscarinic receptors involved in the nervous control of airway smooth muscle tone in the guinea-pig. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The work in this thesis was carried out to investigate modulation of pulmonary sympathetic neurotransmission by endogenous neurotransmitters and autacoids. An in vitro preparation has been developed which allows selective stimulation of post-ganglionic noradrenergic sympathetic nerves innervating airway smooth muscle of the guinea-pig. When the pressure within the fluid-filled tracheal tube had been raised, stimulation of the sympathetic nerve trunk evoked a relaxation response. Sympathetic nerve-induced relaxations were reduced in the presence of muscarinic agonists in a dose-dependent manner, when compared to those obtained at the same intraluminal pressure in the presence of the stable thromboxane analogue U46619, prostaglandin F2a and histamine. These differences were not due to differences in postjunctional "physiological" antagonism, as noradrenaline attenuated the postjunctional contractile actions of U46619 and acetylcholine to a similar extent. These results suggest a prejunctional inhibitory action of muscarinic agonists on sympathetic neurotransmission. This suggestion was confirmed with muscarinic antagonists. The selective M2 antagonists did not alter the postjunctional action of acetylcholine, nor its inhibitory effect on sympathetic nerve-induced relaxations. In contrast, the inhibitory effect of acetylcholine could be blocked with atropine and with M3 muscarinic antagonists. Endogenous acetylcholine was also shown to inhibit sympathetic nerve- induced relaxations. Stimulation of the vagal nerve trunk, simultaneously with sympathetic nerve stimulation caused inhibition of sympathetic nerve-induced relaxations. In addition, the anticholinesterase physostigmine attenuated sympathetic nerve-induced relaxations probably via facilitation of spontaneous acetylcholine release. These results suggest that in the guinea-pig trachea, acetylcholine released from the adjacent parasympathetic nerves inhibits sympathetic neurotransmission via an action on prejunctional muscarinic receptors situated on the noradrenergic nerve terminals. These heteroreceptors appear to be similar to the airway smooth muscle M3 receptors and differ from the M2 autoreceptors on parasympathetic nerve terminals. The implication of these results for the rational design of antimuscarinic drugs is discussed.

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