Dual effect of the muscarinic agonist McN-A-343 on vascular neuroeffector transmission.

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The site and mechanism of action of McN-A-343 (4-m-chlorophenylcarbamoyloxy)-2-butynyltrime-thylammonium chloride) on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10(-6) - 3 x 10(-5) M) of McN-A-343 and cocaine enhanced (up to 210 and 236%, respectively) the contractions evoked by electrical-field stimulation, while higher concentrations (10(-4) -3 x 10(-4)M) inhibited them. McN-A-343 (10(-4)M) caused an initial transitory potentiation (222% of control) of the stimulation-evoked contractions followed by an inhibition. In the presence of cocaine (3 x 10(-5)M), the potentiation caused by McN-A-343 was prolonged and the secondary inhibitory phase was thus abolished. Physostigmine (10(-5) - 10(-4)M), hexamethonium (10(-5) M), atropine (3 x 10(-7) M), suprofen (10(-5) M), and 4-aminopyridine did not alter the effect of McN-A-343 (1-(-4)M). Cocaine (3 x 10(-5)M) and (+)-amphetamine (10(-5) M) reversed the McN-A-343-evoked block, while they did not alter the inhibition caused by tetracaine (3.2 x 10(-5) M). Atropine (3 x 10(-7) M) had no effect on the McN-A-343-induced block, while 4-aminopyridine (10(-4) M) caused a partial and transitory reversal. On the aorta McN-A-343 (10(-4)M) did not alter the contractile concentration-response curve of (-)-noradrenaline (10(-9) - 3 x 10(-4)M), while that of serotonin (10(-8) - 3 x 10(-5)M) was moved to the right in a competitive manner. McN-A-343 (10(-4)M) did not alter the contractions evoked by noradrenaline (10(-7) M) during the period corresponding to the stimulation-evoked enhancement and subsequent inhibition. McN-A-343 (10(-4)M) slightly antagonized the contractions caused by tyramine (10(-6) - 10(-3) M) and carbachol (10(-6) - 10(-3) M). It is concluded that McN-A-343 enhances stimulation-evoked transmitter release by a presynaptic facilitatory action mediated via receptors localized on the outer surface of adrenergic neurones and to a lesser extent by inhibition of noradrenaline re-uptake. The enhancement does not involve presynaptic nicotine or muscarine receptors. Furthermore, McN-A-343 inhibits transmitter release by acting as an adrenergic neurone blocking agent at an intraneuronal site. The inhibition does not involve presynaptic muscarine inhibitory receptors and is prostaglandin-independent.