Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity

P>1. Pancuronium, cisatracurium and vecuronium are antinicotinic agents that, in contrast with d-tubocurarine and hexamethonium, exhibit anticholinesterase activity. Pancuronium-, cisatracurium- and vecuronium-induced fade results from blockade of facilitatory nicotinic receptors on motor nerves, but fade produced by such agents also depends on the presynaptic activation of inhibitory muscarinic M-2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A(1) receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A(2A) receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM 241385, an antagonist of presynaptic facilitatory A(2A) receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve-diaphragm (PND) preparation. 2. The muscles were stimulated indirectly at 75 +/- 3 Hz to induce a sustained tetanizing muscular contraction. The lowest concentration at which each antinicotinic agent produced fade without modifying initial tetanic tension (presynaptic action) was determined. 3. d-Tubocurarine-induced fade occurred only at 55 nmol/L, a concentration that also reduced maximal tetanic tension (post-synaptic action). At 10 nmol/L, ZM 241385 alone did not produce fade, but it did attenuate pancuronium (0.32 mu mol/L)-, cisatracurium (0.32 mu mol/L)- and vecuronium (0.36 mu mol/L)-induced fade. 4. The fade induced by the 'pure' antinicotinic agents d-tubocurarine (55 nmol/L) and hexamethonium (413 mu mol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A(2A) receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity.