The interaction of McN-A-343 with pirenzepine and other selective muscarine receptor antagonists at a prejunctional muscarine receptor

Abstract

The effect of several muscarine receptor antagonists on responses to carbachol (CCh) and McN-A-343 (McN) were compared in the perfused rabbit ear artery preparation stimulated via noradrenergic nerves at 3 Hz in the presence of cocaine (10 microM) and yohimbine (1 microM). The slope of the dose-response curve to McN was significantly less (P less than 0.05) than that for CCh although both agonists produced up to 100% inhibition of responses to nervous stimulation. All the antagonists investigated produced parallel shifts of the dose-response curve to the agonists and atropine, fenipramide or stercuronium gave a similar pA2 value with either agonist. Pirenzepine was a competitive antagonist when CCh was used, as judged by a slope of 0.96 +/- 0.10 for the Arunlakshana-Schild (A-S) plot (pKB 6.2). Displacement of 3H-(-)QNB binding by pirenzepine gave a pKI value of 6.0 which was not significantly different to the pKB value. When McN was used as the agonist, the dose-ratios obtained with pirenzepine (0.5 microM) were significantly different (P less than 0.01) to those with CCh as agonist and the slope of the A-S plot over the concentration range of 0.1 to 3 microM was significantly less than 1.0 (P less than 0.01), indicating that the inhibition was not a simple competitive interaction. It is suggested that the interaction of McN and pirenzepine may involve an allosteric mechanism.

SELECTIVE INHIBITION OF RESPONSES TO CARBACHOL AND McN‐A‐343 IN THE RABBIT VAS DEFERENS

“…This finding is in contrast to that obtained with the prejunctional muscarine receptors on the sympathetic nerves in the rabbit ear artery where pirenzepine exhibited an approximately 20-fold higher affinity for the receptor involved in the inhibitory response to McN compared with that for CCh (Choo et al 1985).…”

A quantitative study of the effects of some muscarinic antagonists on the guinea‐pig olfactory cortex slice

“…It is important to note that the muscarinic receptors described in our study are most probably located presynaptically on terminals of the lateral olfactory tract . Although several studies have suggested that presynaptic receptors in other areas of the nervous system are of the M2-type, these appear to be located on cholinergic terminals (Choo et al, 1985;North et al, 1985). For non-cholinergic terminals, receptors appear to be of the M -type (Raiteri et al, 1984;De Belleroche & Gardinier, 1985), and our data would support these findings.…”

Interaction of some muscarinic agonists and antagonists at the prejunctional muscarinic receptor in the rabbit ear artery preparation

“…It was previously reported (Choo et al, 1985) that pirenzepine is a more selective antagonist of responses to McN-A-343 than of responses to carbachol or acetylcholine. As tetramethylammonium, like McN-A-343, exhibited a concentration-response relationship that was less steep than for other agonists, the effect of antagonists on responses to tetramethylammonium was investigated further.…”

“…I cm long) of the central ear artery was removed from the ear of a rabbit and perfused as previously described by Choo et al (1985). Briefly, the isolated artery was cannulated at both ends and perfused at 1-3 ml min -'with McEwen's solution (McEwen, 1956) containing cocaine (10 AtM) and yohimbine (1 pM) while mounted on a plastic holder in a IOml organ bath filled with the same solution.…”

“…Furthermore, the muscarinic receptor antagonist, pirenzepine, was a more potent inhibitor of responses to McN-A-343 in the ear artery than of those to carbachol (Choo et al, 1985). In view of these findings, a detailed comparison of the relative potencies of a range of muscarinic receptor agonists was undertaken to characterize further the receptor.…”