Presynaptic muscarinic and adenosine receptors are involved in 2 Hz-induced train-of-four fade caused by antinicotinic neuromuscular relaxants in the rat

Abstract

1. Train-of-four fade (TOF(fade) ) is a clinically useful parameter to monitor the degree of block of neuromuscular transmission in curarized patients. Experimentally, TOF(fade) has been attributed to the blockade of facilitatory nicotinic receptors on motor nerve terminals. There is less information regarding the involvement of coexistent presynaptic receptors (e.g. muscarinic M(1) and M(2) , adenosine A(1) and A(2A) ) in the TOF(fade) produced by antinicotinic agents. 2. In the present study, we evaluated the TOF(fade) caused by antinicotinic neuromuscular relaxants (hexamethonium, d-tubocurarine, vecuronium and rocuronium) as the ratio of the muscle tension produced in the rat diaphragm by the fourth to the first stimulus (T(4) /T(1) ) of a train-of-four stimuli delivered to the phrenic nerve trunk at a frequency of 2 Hz. 3. All antinicotinic agents, except hexamethonium, decreased the amplitude of muscle tension during the first stimulus. Hexamethonium, (5.47 mmol/L), d-tubocurarine- (1.1 μmol/L), vecuronium (4.7 μmol/L)- and rocuronium (9.8 μmol/L)-induced TOF(fade) was attenuated by 10 nmol/L pirenzepine (an M(1) receptor antagonist), 1 μmol/L methoctramine (an M(2) receptor antagonist) and 2.5 nmol/L 1,3-dipropyl-8-cyclopentylxanthine (an A(1) receptor antagonist). Blockade of the A(2A) receptor with 10 nmol/L ZM241385 partially reversed the TOF(fade) induced by d-tubocurarine, vecuronium and rocuronium, but not that caused by the 'pure' neuronal nicotinic receptor antagonist hexamethonium, unless one increased the concentration of ZM241385 to 50 nmol/L. 4. The data indicate that presynaptic M(1) , M(2) , A(1) and A(2A) receptors play a role in neuromuscular TOF(fade) caused by antinicotinic neuromuscular relaxants. Such interplay depends on adenosine tonus and on the affinity of neuromuscular blocking agents for neuronal versus muscular nicotinic receptors.

Effects of presynaptic muscarinic cholinoreceptor blockade on neuromuscular transmission as assessed by the train‐of‐four and the tetanic fade response to rocuronium

“…For example, muscarinic and purinergic receptors interact at presynaptic neuronal sides. Of these receptors, muscarinic facilitatory M 1 and inhibitory M 2 receptors regulate the fine‐tuning actions of ACh release on neuronal firing, and these receptors are in turn regulated by purinergic receptors …”

<b>Atropine is more efficient than ZM241385 to reduce a drastic level of fade caused by cisatracurium at 50 Hz

“…These data indicate that a higher activation of M 1 receptors on motor nerve by acetylcholine might be occurring in the cisatracurium-induced 100% Fade. It has already been demonstrated that A-value is influenced by presynaptic M 1 receptors activity when the motor nerve is stimulated at 50.00 Hz trains (Oliveira, Timóteo & Sá, 2002 cisatracurium-induced Fade would be the expected effect when the preparations were previously treated with ZM241385 (Oliveira et al, 2002;Pereira et al, 2012), it was supposed that the anticholinesterase activity of cisatracurium (Bornia et al, 2009;Bornia et al, 2011;Pereira et al, 2011) in the experimental condition causing 100% Fade reduced the expression of facilitatory effect induced by the blockade of A 2A receptors by producing a level of M 1 /M 2 activation by acetylcholine higher than that determined by the separate treatment of preparations with cisatracurium. Indeed, the previous treatment of preparations with ZM241385 caused a reduction in the A-value induced by cisatracurium which was not significantly (p > 0.05) different from that obtained after the administration of cisatracurium.…”

“…conditions of neuromuscular transmission, as different patterns of stimulation applied on motor nerve in the absence or in the presence of drugs, may modify the autoregulatory cholinergic (facilitatory-nicotinic receptors expressing α3β2 subunits, facilitatory-M 1 and inhibitory-M 2 subtypes of muscarinic receptors) and the modulatory (facilitatory-A 2A and inhibitory-A 1 adenosine receptors) mechanisms on the terminal (Bornia, Bando, Machinsky, Pereira, & Prado, 2009;Pereira, Bornia, Sá, & Prado, 2011). Therefore, the Fade caused by antinicotinic (hexamethonium) agent may be severe (~ 89%) when the concentration of such agent is causing 25% TOF fade (Pereira, Sá, & Prado, 2012).…”

Adenosine A2Areceptor antagonists are broad facilitators of antinicotinic neuromuscular blockade monitored either with 2-Hz train-of-four or 50-Hz tetanic stimuli

“…Previous studies from our group found differences in the magnitude of tetanic fade and TOF fade produced by distinct antinicotinic muscular relaxants. 9,15,16 Uncertainty about the usefulness of the TOF ratio to control safe recovery from curarization 17 prompted us to investigate the participation of presynaptic muscarinic (M 1 and M 2 ) and adenosine (A 1 and A 2A ) receptors on tetanic fade (50 Hz) produced by antinicotinic muscle relaxants (i.e. D-tubocurarine, pancuronium and cisatracurium) used at concentrations that cause a 25% reduction of the TOF ratio in the rat isolated phrenic nervehemidiaphragm preparation.…”

“…D-tubocurarine, pancuronium and cisatracurium) used at concentrations that cause a 25% reduction of the TOF ratio in the rat isolated phrenic nervehemidiaphragm preparation. 16…”