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Blockade of neuronal facilitatory nicotinic receptors containing alpha 3 beta 2 subunits contribute to tetanic fade in the rat isolated diaphragm.

Abstract
Nicotinic receptor (nAChR) subtypes involved in pre- and postjunctional actions underlying tetanic fade were studied in rat phrenic-nerve hemidiaphragms. We investigated the ability of subtype-specific nAChR antagonists to depress nerve-evoked contractions and [(3)H]-acetylcholine ([(3)H]-ACh) release. Muscle tension was transiently increased during brief high frequency trains (50 Hz for 5 sec). The rank potency order of nAChR antagonists to reduce tetanic peak tension was alpha-bungarotoxin > d-tubocurarine >> mecamylamine > hexamethonium. Reduction of maximal tetanic tension produced by dihydro-beta-erythroidine (0.03-10 microM), methyllycaconitine (0.003-3 microM), and alpha-conotoxin MII (0.001-0.3 microM) did not exceed 30%. Besides reduction of peak tension d-tubocurarine (0.1-0.7 microM), mecamylamine (0.1-300 microM), and hexamethonium (30-3,000 microM) also caused tetanic fading. With alpha-conotoxin MII (0.001-0.3 microM) and dihydro-beta-erythroidine (0.03-10 microM), tetanic fade was evident only after decreasing the safety factor of neuromuscular transmission (with high magnesium ions, 6-7 mM). The antagonist rank potency order to reduce evoked (50 Hz for 5 sec) [(3)H]-ACh release from motor nerve terminals was alpha-conotoxin MII (0.1 microM) > dihydro-beta-erythroidine (1 microM) approximately d-tubocurarine (1 microM) > mecamylamine (100 microM) > hexamethonium (1,000 microM). When applied in a concentration (0.3 microM) above that producing tetanic paralysis, alpha-bungarotoxin failed to affect [(3)H]-ACh release. Data obtained suggest that postjunctional neuromuscular relaxants interact with alpha-bungarotoxin-sensitive nicotinic receptors containing alpha1-subunits, whereas blockade of neuronal alpha3beta2-containing receptors produce tetanic fade by breaking nicotinic autofacilitation of acetylcholine release.
AuthorsMiguel Faria, Laura Oliveira, M Alexandrina Timóteo, M Graça Lobo, Paulo Correia-De-Sá
JournalSynapse (New York, N.Y.) (Synapse) Vol. 49 Issue 2 Pg. 77-88 (Aug 2003) ISSN: 0887-4476 [Print] United States
PMID12740863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2003 Wiley-Liss, Inc.
Chemical References
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • nicotinic receptor alpha3beta2
  • Acetylcholine
Topics
  • Acetylcholine (metabolism)
  • Animals
  • Diaphragm (drug effects, metabolism, physiology)
  • Dose-Response Relationship, Drug
  • Female
  • Male
  • Muscle Contraction (drug effects, physiology)
  • Neurons (drug effects, physiology)
  • Nicotinic Antagonists (pharmacology)
  • Rats
  • Rats, Wistar
  • Receptors, Nicotinic (physiology)

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