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CK Buckner, D Dea, N Liberati and RD Krell
Department of Pharmacology, ICI Pharmaceuticals Group, ICI Americas Inc., Wilmington, Delaware 19897.
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)
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