Distinct mixtures of muscarinic receptor subtypes mediate inhibition of noradrenaline release in different mouse peripheral tissues, as studied with receptor knockout mice

1 The muscarinic heteroreceptors modulating noradrenaline release in atria, urinary bladder and vas deferens were previously studied in mice in which the M2 or the M4 muscarinic receptor genes had been disrupted. These experiments showed that these tissues possessed both M2 and non‐M2 heteroreceptors. The analysis was now extended to mice in which either the M3, both the M2 and the M3, or both the M2 and the M4 genes had been disrupted (M3‐knockout, M2/3‐knockout and M2/4‐knockout). Tissues were preincubated with 3H‐noradrenaline and then stimulated electrically (20 pulses per 50 Hz). 2 In wild‐type atria, carbachol (0.01–100 μM) decreased the electrically evoked tritium overflow by maximally 60–78%. The maximum inhibition of carbachol was reduced to 57% in M3‐knockout and to 23% in M2/4‐knockout atria. Strikingly, the effect of carbachol was abolished in M2/3‐knockout atria. 3 In wild‐type bladder, carbachol (0.01–100 μM) reduced the evoked tritium overflow by maximally 57–71%. This effect remained unchanged in the M3‐knockout, but was abolished in the M2/4‐knockout bladder. 4 In wild‐type vas deferens, carbachol (0.01–100 μM) reduced the evoked tritium overflow by maximally 34–48%. The maximum inhibition of carbachol was reduced to 40% in the M3‐knockout and to 18% in the M2/4‐knockout vas deferens. 5 We conclude that the postganglionic sympathetic axons of mouse atria possess M2 and M3, those of the urinary bladder M2 and M4, and those of the vas deferens M2, M3 and M4 release‐inhibiting muscarinic receptors. British Journal of Pharmacology (2005) 145, 1153–1159. doi:10.1038/sj.bjp.0706297