Interaction of the neuromuscular blocking drugs alcuronium, decamethonium, gallamine, pancuronium, ritebronium, tercuronium and d-tubocurarine with muscarinic acetylcholine receptors in the heart and ileum

Abstract

Neuromuscular blocking drugs have a high affinity for muscarinic acetylcholine receptors in the heart atria and ileal smooth muscle. In experiments on homogenates, alcuronium, gallamine, pancuronium, tercuronium and ritebronium inhibited the binding of the muscarinic antagonist (3H)quinuclidinyl benzilate (QNB) to rat heart atria with IC50 values of 0.15-0.53 mumol X 1(-1) and to ileal longitudinal muscles with IC50 values of 0.12-0.45 mumol X 1(-1). d-Tubocurarine and decamethonium inhibited (3H)QNB binding to these tissues with IC50 values of 6.2-8.5 mumol X 1(-1). For each neuromuscular blocking drug, the IC50 values were virtually identical for (3H)QNB displacement in the homogenates of the atria and of the ileal muscle. Alcuronium and gallamine differed from the other blocking agents in that they produced less steep (3H)QNB displacement curves both in the atria and the ileal muscle; Hill coefficients for the binding of alcuronium and gallamine to atrial and ileal homogenates were lower than unity. On isolated atria, gallamine, pancuronium, ritebronium and tercuronium antagonized the inhibition of tension development caused by the muscarinic agonist, methylfurmethide, with Kd values which were of the same order of magnitude as the IC50 values for the displacement of (3H)QNB binding to homogenates; the Kd of alcuronium was 12.5 times higher. d-Tubocurarine and decamethonium did not antagonize the effects of methylfurmethide at concentrations up to 100 mumol X 1(-1). On isolated ileal longitudinal muscle, gallamine and pancuronium antagonized the effects of methylfurmethide with Kd values that were 53 times and 100 times higher than their respective Kd values in the atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Two populations of muscarinic binding sites in the chick heart distinguished by affinities for ligands and selective inactivation

“…We have found earlier that the neuromuscular blocker, alcuronium interacts allosterically with muscarinic receptors (Nedoma et al, 1985; and increases the specific binding of [3H]-NMS in rat heart, smooth muscle and cerebellum, but not in cerebral cortex and salivary gland (Tucek et al, 1990). This variation in the effect of alcuronium with tissue location is consistent with the distribution of M2 receptors and suggests that the drug's positive allosteric action is selective for the M2 receptor subtype.…”

Pharmacological differences between two muscarinic responses of the rat superior cervical ganglion in vitro

“…The concentrations of gallamine and pancuronium used in these experiments were selected to inhibit cardiac-like (M2) receptors but have minimal actions on corticallike (M,) receptors (Dalton & Tyers, 1982;Stockton et al, 1983;Nedoma et al, 1985).…”

Muscarinic receptors mediating suppression of the M‐current in guinea‐pig olfactory cortex neurones may be of the M2‐subtype

“…Under current-clamp, this action would be manifest as a slow membrane depolarization and increase in cell input resistance. The muscarinic suppression of IM was not blocked by low concentrations of pirenzepine (up to 300 nM), pre-applied for at least 20 min (Figure lA b,c), whereas gallamine (20 gM), a 'cardioselective' M2-receptor antagonist (Hammer & Giachetti, 1984;Nedoma et al, 1985), produced a clear inhibition of the action of muscarine ( Figure lAd). Higher concentrations of pirenzepine (500 nM-l M) did, however, exhibit an anti-muscarinic effect (not illustrated …”

“…A further subclassification of the peripheral M2-receptor has also been suggested in view of the fact that certain skeletal neuromuscular blockers e.g. gallamine, show more selective anti-muscarinic effects on the heart (Nedoma et al, 1985), whereas antagonists such as 4-diphenyl-acetoxy-N-methylpiperidine (4-DAMP) show a relatively higher affinity for the ileal muscarinic receptor (Barlow et al, 1976). Recent intracellular studies on mammalian central neurones have suggested that both excitatory and inhibitory actions of cholinoceptor agonists can be mediated via M2-muscarinic receptors (Egan & North, 1985;McCormick & Prince, 1986a (Constanti & Galvan, 1983b evoked a smaller instantaneous step, followed by a decaying inward relaxation to the holding current level.…”