title: Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity.
abstract: 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 M2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A1 receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A2A receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM241385, an antagonist of presynaptic facilitatory A2A receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve-diaphragm (PND) preparation. 2. The muscles were stimulated indirectly at 75±3Hz 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 μmol/L)-, cisatracurium (0.32 μmol/L)- and vecuronium (0.36 μmol/L)-induced fade. 4. The fade induced by the 'pure' antinicotinic agents d-tubocurarine (55 nmol/L) and hexamethonium (413 μmol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A2A receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity.
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringa, Paraná, BrazilLaboratory of Pharmacology and Neurobiology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.
authors.forename: Elaine Cs
authors.initials: EC
authors.lastname: Bornia
authors.forename: Paulo
authors.initials: P
authors.lastname: Correia-de-Sá
authors.forename: Wilson
authors.initials: W
authors.lastname: Alves-Do-Prado
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001279:Atracurium / Q000031:analogs & derivatives / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D018738:Hexamethonium / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009465:Neuromuscular Agents / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism; D010197:Pancuronium / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D017661:Receptors, Presynaptic / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014403:Tubocurarine / Q000494:pharmacology; D014673:Vecuronium Bromide / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D009465:Neuromuscular Agents; D043705:Receptor, Adenosine A2A; D043585:Receptor, Muscarinic M2; D011978:Receptors, Nicotinic; D017661:Receptors, Presynaptic; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D001279:Atracurium; D018738:Hexamethonium; D014673:Vecuronium Bromide; D010197:Pancuronium; D000109:Acetylcholine; C101584:cisatracurium; D014403:Tubocurarine