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Heterogeneity of presynaptic muscarinic receptors mediating inhibition of sympathetic transmitter release: a study with M 2 ‐ and M 4 ‐receptor‐deficient mice
Author(s) -
Trendelenburg AnneUlrike,
Gomeza Jesus,
Klebroff Werner,
Zhou Hongxia,
Wess Jürgen
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705053
Subject(s) - muscarinic acetylcholine receptor , carbachol , vas deferens , methoctramine , endocrinology , pirenzepine , medicine , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m4 , muscarinic acetylcholine receptor m3 , muscarinic acetylcholine receptor m1 , chemistry , acetylcholine , muscarinic acetylcholine receptor m5 , physostigmine , receptor , biology
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, M 2 ‐ and M 4 ‐knockout, and the corresponding M 2 ‐ and M 4 ‐wildtype mice, after preincubation with 3 H‐noradrenaline. The muscarinic agonist carbachol decreased evoked tritium overflow (20 pulses/50 Hz) in each tissue and strain investigated. After deletion of the M 2 ‐receptor the maximal inhibition by carbachol was significantly reduced (by 41–72%), but not abolished, in all tissues. After deletion of the M 4 ‐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 M 2 in atria and bladder and probably a mixture of M 2 and M 4 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 M 2 ‐receptors to inhibit noradrenaline release. However, the results do not exclude a minor contribution of M 4 ‐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 M 2 ‐ and non‐M 2 ‐receptors. The non‐M 2 ‐receptors remain unknown in atria and the bladder, and may represent primarily M 4 ‐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