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 similar to 8-10 mV during the first 3 h after nerve section and this early postdenervation depolarization is reduced substantially by the presence of 5 x 10(-8) M acetylcholine (ACh) or carbachol (CB). The muscarinic antagonist atropine (Atr; 5 x 10(-9) to 5 x 10(-6) M) reduced the effect of CB in a dose-dependent manner (K-i = 7 x 10(-8) M) and increased the rate of the early postdenervation depolarization. In lower doses (5 x 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 x 10(-7) mu M. 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. (C) 2000 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.