Muscarinic M1- and M2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens.

Twitch contractions of the rabbit vas deferens elicited by electrical field stimulation were inhibited by tetrodotoxin, guanethidine, bretylium and alpha,beta-methylene-ATP but were unaffected by hexamethonium, physostigmine, 1,1-dimethyl-4-phenylpiperazinium and prazosin, suggesting that they resulted from ATP released following postganglionic sympathetic nerve stimulation. McN-A-343 inhibited but carbachol and several other muscarinic agonists potentiated the twitch contractions; these effects were not modified by hexamethonium or physostigmine. Muscarinic agonists had no effect on the tension in unstimulated organs whereas contractions elicited by ATP, noradrenaline and KCl were potentiated by carbachol but remained unaffected by McN-A-343. The responses of the twitch contractions to McN-A-343 and carbachol were inhibited to different degrees by antimuscarinic drugs: the affinity (pA2) of atropine, secoverine and himbacine against McN-A-343 and carbachol was similar. However, pirenzepine, telenzepine, trihexyphenidyl, dicyclomine and hexahydro-sila-difenidol displayed preferential antagonism of the responses to McN-A-343 whereas the converse was true for AF-DX 116 and gallamine. The highly significant correlation between the pA2 values obtained for 10 antagonists against carbachol responses in rabbit vas deferens and rat left atrium suggests that the receptors may be similar. The data support the presence of a presynaptic M1-receptor mediating inhibition and a postsynaptic, cardiac-like M2-receptor responsible for enhancing neurogenic contractions in rabbit vas deferens.