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

Abstract

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

Contractions of the Mouse Prostate Elicited by Acetylcholine Are Mediated by M3 Muscarinic Receptors

“…In contrast, in both the human (Hedlund et al, 1985) and canine (Arver and Sjöstrand, 1982) prostate, muscarinic receptors produce a slight reduction in noradrenaline release. Likewise, sympathetic neurotransmitter release is inhibited in the mouse atria, urinary bladder, and vas deferens by muscarinic receptors (Trendelenburg et al, 2005). In the present study, atropine had no detectable effect on the contractile response to high concentrations of acetylcholine in prostates taken from M3R(Ϫ/Ϫ) mice, whereas the noncompetitive nicotinic antagonist mecamylamine abolished the contractile response.…”

M2 and M3 muscarinic receptors are involved in enteric nerve-mediated contraction of the mouse ileum: findings obtained with muscarinic-receptor knockout mouse

“…Therefore, it appears that the lack of or the blockade of the M 2 receptor has no influence on contraction of ileal smooth muscle strips induced by SP. There were reports that activation of M 2 receptors regulated the release of several neurotransmitters (32,34,40,42). Our group (31) also reported that M 2 receptors were present on the cholinergic neurons and regulated ACh release from the myenteric plexus.…”

“…In the present study, localization of M 2 receptors on the SP-containing neurons was observed in the myenteric plexus of the mouse ileum. M 4 receptors, in addition to M 2 receptors, have been reported to play a valuable role in regulating the release of neurotransmitters in both the central and peripheral nervous systems (31,34,40). However, M 4 receptors had no role to play in the control of EFS-induced sustained contraction as described above.…”

Muscarinic Receptor Subtypes in the Lower Urinary Tract

“…Interactions between the parasympathetic and sympathetic nervous systems have also been demonstrated in the bladder, i.e. inhibitory muscarinic receptors located on adrenergic nerve terminals inhibit the release of noradrenaline in the rabbit bladder and urethra [69][70][71] . In the rabbit urinary bladder, ␣ 2 -adrenoceptors also inhibit the release of acetylcholine [67] .…”