Heterogeneity of presynaptic muscarinic receptors mediating inhibition of sympathetic transmitter release: a study with M2‐ and M4‐receptor‐deficient mice

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Abstract
Presynaptic muscarinic receptors modulate sympathetic transmitter release. The goal of the present study was to identify the muscarinic receptor subtype(s) mediating inhibition of sympathetic transmitter release in mouse atria, urinary bladder and vas deferens. To address this question, electrically evoked noradrenaline release was assessed using tissue preparations from NMRI, M2- and M4-knockout, and the corresponding M2- and M4-wildtype mice, after preincubation with 3H-noradrenaline. The muscarinic agonist carbachol decreased evoked tritium overflow (20 pulses/50 Hz) in each tissue and strain investigated. After deletion of the M2-receptor the maximal inhibition by carbachol was significantly reduced (by 41–72%), but not abolished, in all tissues. After deletion of the M4-receptor a moderate and significant reduction of the maximal inhibition by carbachol (by 28%) was observed only in the vas deferens. Experiments with the muscarinic antagonists methoctramine and pirenzepine confirmed that the presynaptic muscarinic receptors were predominantly M2 in atria and bladder and probably a mixture of M2 and M4 in the vas deferens. Experiments in the urinary bladder with the cholinesterase inhibitor physostigmine and the muscarinic antagonist ipratropium demonstrated that endogenously released acetylcholine predominantly acted through M2-receptors to inhibit noradrenaline release. However, the results do not exclude a minor contribution of M4-receptors to this endogenous inhibition. In conclusion, our results clearly indicate that the release-inhibiting muscarinic receptors on postganglionic sympathetic axons in mouse atria, bladder and vas deferens represent mixtures of M2- and non-M2-receptors. The non-M2-receptors remain unknown in atria and the bladder, and may represent primarily M4-receptors in the vas deferens. These results reveal an unexpected heterogeneity among the muscarinic receptors mediating inhibition of noradrenaline release. British Journal of Pharmacology (2003) 138, 469–480. doi:10.1038/sj.bjp.0705053