Blockade of neuronal facilitatory nicotinic receptors containing alpha 3 beta 2 subunits contribute to tetanic fade in the rat isolated diaphragm.
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.
Faria
Miguel
M
Laboratório de Farmacologia, Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4099-003 Porto, Portugal.
Oliveira
Laura
L
Timóteo
M Alexandrina
MA
Lobo
M Graça
MG
Correia-De-Sá
Paulo
P
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000502:physiology*
D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C419362:nicotinic receptor alpha3beta2; D000109:Acetylcholine