Adenosine A2A receptor antagonists are broad facilitators of antinicotinic neuromuscular blockade monitored either with 2 Hz train-of-four or 50 Hz tetanic stimuli
Article first published online: 26 SEP 2012
© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd
Clinical and Experimental Pharmacology and Physiology
Volume 39, Issue 10, pages 869–877, October 2012
How to Cite
Pereira, M. W., Correia-de-Sá, P. and Alves-Do-Prado, W. (2012), Adenosine A2A receptor antagonists are broad facilitators of antinicotinic neuromuscular blockade monitored either with 2 Hz train-of-four or 50 Hz tetanic stimuli. Clinical and Experimental Pharmacology and Physiology, 39: 869–877. doi: 10.1111/j.1440-1681.2012.12004.x
- Issue published online: 26 SEP 2012
- Article first published online: 26 SEP 2012
- Manuscript Accepted: 14 AUG 2012
- Manuscript Revised: 10 AUG 2012
- Manuscript Received: 16 MAY 2012
- Araucaria Foundation and Foundation of Research
- train-of-four fade
- The 2 Hz train-of-four ratio (TOFratio) is used to monitor the degree of patient curarization. Using a rat phrenic nerve–hemidiaphragm preparation, we showed that antinicotinic agents, such as hexamethonium, d-tubocurarine and pancuronium, but not cisatracurium, decreased contractions produced by physiological nerve activity patterns (50 Hz) more efficiently than those caused by 2 Hz trains. Uncertainty about the usefulness of the TOFratio to control safe recovery from curarization prompted us to investigate the muscarinic and adenosine neuromodulation of tetanic (50 Hz) fade induced by antinicotinic agents at concentrations that cause a 25% reduction in the TOFratio (TOFfade).
- Tetanic fade caused by d-tubocurarine (1.1 μmol/L), pancuronium (3 μmol/L) and hexamethonium (5.47 mmol/L) was attenuated by blocking presynaptic inhibitory muscarinic M2 and adenosine A1 receptors with methoctramine (1 μmol/L) and 1,3-dipropyl-8-cyclopentylxanthine (2.5 nmol/L), respectively. These compounds enhanced rather than decreased tetanic fade induced by cisatracurium (2.2 μmol/L), but they consistently attenuated cisatracurium-induced TOFfade. The effect of the M1 receptor antagonist pirenzepine (10 nmol/L) on fade produced by antinicotinic agents at 50 Hz was opposite to that observed with TOF stimulation. Blockade of adenosine A2A receptors with ZM 241385 (10 nmol/L) attenuated TOFfade caused by all antinicotinic drugs tested, with the exception of the ‘pure’ presynaptic nicotinic antagonist hexamethonium. ZM 241385 was the only compound tested in this series that facilitated recovery from tetanic fade produced by cisatracurium.
- The data suggest that distinct antinicotinic relaxants interfere with fine-tuning neuromuscular adaptations to motor nerve stimulation patterns via activation of presynaptic muscarinic and adenosine receptors. These results support the use of A2A receptor antagonists together with atropine to facilitate recovery from antinicotinic neuromuscular blockade.