Carbachol and acetylcholine delay the early postdenervation depolarization of muscle fibres through M1-cholinergic receptors

The resting membrane potential (RMP) of denervated muscle fibres of rat diaphragm muscle is depolarized by ∼8–10 mV during the first 3 h after nerve section and this early postdenervation depolarization is reduced substantially by the presence of 5×10 −8 M acetylcholine (ACh) or carbachol (CB). The muscarinic antagonist atropine (Atr; 5×10 −9 to 5×10 −6 M) reduced the effect of CB in a dose-dependent manner ( K i=7×10 −8 M) and increased the rate of the early postdenervation depolarization. In lower doses (5×10 −7 M), Atr acted only in the presence of an allosteric stabilizator hexamethylene-bis-[dimethyl-(3-phtalimidopropyl)ammonium] (W-84). Also pirenzepine, a specific inhibitor of the M1 subtype of muscarinic receptor, blocked the action of CB in a dose-dependent manner with an apparent inhibition constant K i=1×10 −7 μM. DAMP, a specific M3 antagonist, was without effect on the muscle hyperpolarization induced by CB. CB also hyperpolarized the membrane potentials of muscles which were denervated for 1–3 days. It is concluded that ACh and CB protect the muscle fibres from early depolarization through M1-cholinergic receptors on the muscle membrane. These particular receptors can apparently mediate the ‘trophic’, non-impulse regulation of RMP in skeletal muscles when they are activated by acetylcholine released non-quantally.