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.
Laboratório de Farmacologia, Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4099-003 Porto, Portugal.
Miguel
M
Faria
Laura
L
Oliveira
M Alexandrina
MA
Timóteo
M Graça
MG
Lobo
Paulo
P
Correia-De-Sá
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