1 McNeil A 343 (10-mu-M-30-mu-M) enhanced the fractional stimulation-induced (S-I) outflow of radioactivity from mouse isolated atria which had been incubated with [H-3]-noradrenaline. The enhancing effect of McNeil A 343 was not altered by hexamethonium (300-mu-M) suggesting that it was not due to an action at nicotinic receptors. It is also unlikely that McNeil A 343 enhanced the S-I outflow of radioactivity in mouse atria by blocking neuronal reuptake of noradrenaline since the effect persisted in the presence of cocaine (30-mu-M). 2 The facilitatory effect of McNeil A 343 on the S-I outflow of radioactivity was attenuated by atropine (0.3-mu-M), pirenzepine (0.2-mu-M or 1.0-mu-M), dicyclomine (1.0-mu-M) and methoctramine (1.0-mu-M) and was thus due to activation of muscarinic receptors. 3 In contrast to the effect of McNeil A 343, another muscarinic receptor agonist, carbachol (3.0-mu-M) significantly decreased the S-I outflow of radioactivity. The receptors through which McNeil A 343 acts to enhance the S-I outflow of radioactivity appear to be distinct from inhibitory prejunctional muscarinic receptors. The relatively M1-selective antagonist, pirenzepine (0.2-mu-M), attenuated the facilitatory effect of McNeil A 343 whereas a higher concentration (1.0-mu-M) was required to block the inhibitory effect of carbachol. Conversely, the relatively M2-selective antagonist, methoctramine (0.1-mu-M), blocked the inhibitory effect of carbachol but a higher concentration of methoctramine (1.0-mu-M) was required to block the facilitatory effects of McNeil A 343. These results tentatively ascribe facilitatory muscarinic receptors as belonging to the M1 subtype and inhibitory muscarinic receptors as belonging to the M2 subtype. 4 The non-selective muscarinic receptor antagonist, atropine, enhanced the S-I outflow of radioactivity, suggesting that there was tonic activation of inhibitory prejunctional muscarinic receptors by endogenous acetylcholine released from parasympathetic nerves. However, pirenzepine (0.03-mu-M-1.0-mu-M) did not decrease the S-I outflow of radioactivity, suggesting that under the conditions of the present study, facilitatory muscarinic receptors are not tonically activated by endogenous acetylcholine.
