A pharmacologic examination of receptors mediating serotonin-induced bronchoconstriction in the anesthetized guinea pig.
The receptors involved in the bronchoconstriction evoked in vivo by intravenous administration to the anesthetized guinea pig of serotonin and serotonin-related agonists have been examined in this study. Animals were pretreated with indomethacin and (+/-)-propranolol to inhibit cyclooxygenase and beta adrenergic receptors, respectively, and pulmonary parameters were obtained with a Buxco pulmonary mechanics computer. Dose-dependent increases in pulmonary resistance and decreases in dynamic lung compliance were produced by serotonin, 2-methyl-serotonin, 5-methoxy-tryptamine, alpha-methyl-serotonin, 5-carboxamidotryptamine, and m-trifluoromethylphenylpiperazine (TFMPP). Responses to all agonists except 2-methyl-serotonin, a selective 5-hydroxytryptamine3 (5-HT3) agonist, were antagonized by the 5-HT2 antagonists, LY53857 and ketanserin. Zaclopride, 1 and 10 mg/kg, a selective 5-HT3 antagonist, blocked responses to 2-methyl-serotonin. A maximally effective dose of LY53857 (1 mg/kg) produced larger shifts of the dose-response curves to serotonin, 5-methoxytryptamine and alpha-methyl-serotonin than did a maximally effective dose of ketanserin (1 mg/kg). Thiorphan, 10 mg/kg, an inhibitor of neutral endopeptidase, potentiated 2-methyl-serotonin and, when studied in the presence of LY53857, also potentiated serotonin, 5-methoxytryptamine and TFMPP. After thiorphan and LY53857, responses to serotonin, but not 5-methoxytryptamine or TFMPP, were blocked by zaclopride. Capsaicin pretreatment of the animals resulted in rightward shifts of the dose-response curves to serotonin, 2-methyl-serotonin and TFMPP, but not to 5-methoxytryptamine or alpha-methyl-serotonin. Potentiation by thiorphan and antagonism by zaclopride of responses to serotonin were still evident after capsaicin pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Buckner
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Department of Pharmacology, ICI Pharmaceuticals Group, ICI Americas Inc., Wilmington, Delaware 19897.
Dea
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Liberati
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Krell
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D000758:Anesthesia; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016084:Bronchoconstriction / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D015244:Thiorphan / Q000494:pharmacology
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004873:Ergolines; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C018406:1-(3-trifluoromethylphenyl)piperazine; D012701:Serotonin; D001285:Atropine; C055971:zacopride; D015244:Thiorphan; D011738:Pyrilamine; C032663:LY 53857; D002211:Capsaicin