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‐chlorophenylcarbamoyloxy)‐2‐butynyltrime‐thylammonium chloride) on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10−6 — 3 × 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 × 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 × 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 × 10−7 M), suprofen (10−5 M), and 4‐aminopyridine did not alter the effect of McN‐A‐343 (10−4 M). Cocaine (3 × 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 × 10−5 M). Atropine (3 × 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 × 10−4 M), while that of serotonin (10−8 — 3 × 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.