Dual Effect of the Muscarinic Agonist McN-A-343 on Vascular Neuroeffector Transmission

Abstract

The site and mechanism of action of McN-A-343[(4-m-chlorophenylcarbamoyloyxy)-2-butynyltrimethylammonium chloride] on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10-6-3 .times. 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 .times. 104 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 .times. 10-5 M), the potentiation caused by McN-A-343 was prolonged and the secondary inhibitory phase was thus abolished. Physostigmine (10-5 to 10-4 M), hexamethonium (10-5 M), atropine (3 .times. 10-7 M), suprofen (10-5 M) and 4-aminopyridine did not alter the effect of McN-A-343 (10-4 M). Cocaine (3 .times. 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 .times. 10-5 M). Atropine (3 .times. 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 [norepinephrine] (10-9-3 .times. 10-4 M), while that of serotonin (10-8-3 .times. 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 to 10-3 M) and carbachol (10-6 to 10-3 M). Evidently McN-A-343 enhances stimulation-evoked transmitter release by a presynaptic facilitatory action mediated via receptors localized on the outer surface of adrenergic neurons and to a lesser extent by inhibition of noradrenaline re-uptake. The enhancement does not involve presynaptic nicotine or muscarine receptors. McN-A-343 inhibits transmitter release by acting as an adrenergic neuron blocking agent at an intraneuronal site. The inhibition does not involve presynaptic muscarine inhibitory receptors and is prostaglandin-independent.