title: Paradoxical neostigmine-induced TOFfade: on the role of presynaptic cholinergic and adenosine receptors.
abstract: Neuromuscular transmission is clinically monitored using the train-of-four ratio (TOFratio), which is the quotient between twitch tension produced by the fourth (T4) and by the first (T1) stimulus within a train-of-four stimulation at 2Hz. Neostigmine causes a paradoxical depression of the TOFratio (TOFfade) that is amplified by intra-arterial atropine in cats. This led us to question the usefulness of the TOFratio as a sole testing element to control neostigmine-induced reversal of neuromuscular transmission block caused by non-depolarizing agents. We hypothesized that the inhibition of cholinesterase activity might increase acetylcholine bioavailability and consequently cholinoceptor activation, leading to concomitant adenosine release from nerve endings and skeletal muscle fibers. The involvement of presynaptic muscarinic and adenosine receptors in neostigmine-induced TOFfade in the rat phrenic nerve diaphragm was investigated. Blockade of adenosine A2A receptors with ZM241385 and of muscarinic M2 receptors with methoctramine or atropine amplified neostigmine-induced TOFfade. Notwithstanding TOFfade amplification, the blockade of M2 or A2A receptors increased both T1 and T4 twitch tensions above control during the first 3min of neostigmine application. Beyond that period, the T1 twitch tension returned to baseline, whereas T4 decreased further until the control value with neostigmine alone. Blockade of M1 receptors by pirenzepine did not change neostigmine-induced TOFfade, unless A2A receptors were concurrently blocked with ZM241385. Data indicate that the paradoxical neostigmine-induced fade involves presynaptic mechanisms that regulate transmitter release and synaptic adenosine accumulation, including the activation of adenosine A2A and muscarinic M2 receptors.
authors.affiliation: Department of Pharmacology and Therapeutic, State University of Maringá, Paraná, Brazil.
authors.forename: Edivan
authors.initials: E
authors.lastname: de Paula Ramos
authors.affiliation: Department of Pharmacology and Therapeutic, State University of Maringá, Paraná, Brazil.
authors.forename: Marilia Bordignon
authors.initials: MB
authors.lastname: Antônio
authors.affiliation: Department of Physiology, State University of Maringá, Paraná, Brazil.
authors.forename: Celia Regina
authors.initials: CR
authors.lastname: Ambiel
authors.affiliation: Laboratório de Farmacologia e Neurobiologia/UMIB, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Correia-de-Sá
authors.affiliation: Department of Pharmacology and Therapeutic, State University of Maringá, Paraná, Brazil. Electronic address: waprado@uem.br.
authors.forename: Wilson
authors.initials: W
authors.lastname: Alves-Do-Prado
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003959:Diamines / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009388:Neostigmine / Q000494:pharmacology*; D010791:Phrenic Nerve / Q000187:drug effects* / Q000502:physiology; D010890:Pirenzepine / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011950:Receptors, Cholinergic / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000502:physiology; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D003959:Diamines; D018727:Muscarinic Antagonists; D058915:Purinergic P1 Receptor Antagonists; D011950:Receptors, Cholinergic; D017661:Receptors, Presynaptic; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D009388:Neostigmine; D010890:Pirenzepine; D001285:Atropine; C054938:methoctramine
keywords: Adenosine receptors; Fade; Muscarinic receptors; Neostigmine; Train-of-four