Serotonin induces constriction and relaxation of the guinea pig airway.
The response of guinea pig trachea to 5-hydroxytryptamine (serotonin; 5-HT) was investigated by studying tracheal strips suspended in organ chambers for isometric tension measurements. Serotonin concentrations of 0.1 to 10 microM produced concentration-dependent contractions, whereas at higher concentrations (10-300 microM) the agonist caused concentration-dependent relaxations. The 5-HT2 antagonist ketanserin shifted the bimodal 5-HT response-curve to the right (pA2 for ketanserin was 8.98). The 5-HT1A agonist, (+)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide and 5-HT3 antagonist, ICS 205930 (3-tropanyl-indole-3-carboxylate) had no effect on the 5-HT-response curve. Incubation with atropine resulted in a depression of the maximal contractility and an increase in the EC50 without changing the bimodal nature of the concentration-response curve. Hexamethonium was able to block the atropine effect without significantly affecting the 5-HT concentration-response curve. Neither the constriction nor the relaxation was altered by propranolol, chlorpheniramine or capsaicin pretreatment. Histamine and carbachol preconstricted airways were also relaxed by 5-HT in a concentration-dependent fashion and this relaxation was antagonized by ketanserin (pKb for ketanserin in histamine preconstricted airways was 9.4). Epithelial denudation did not inhibit the 5-HT-induced relaxation. 5-HT stimulated inositol-monophosphate production which also exhibited a bimodal response and correlated well with the functional response. The above findings suggest that 5-HT causes both constriction and relaxation of the guinea pig airway, and that both responses are antagonized by a 5-HT2 receptor blocker. In addition, part of the constrictor response of 5-HT is mediated through a cholinergic preganglionic pathway. Finally, inositol-monophosphate production induced by 5-HT correlates with the functional response.
Baumgartner
R A
RA
Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland.
Wills-Karp
M
M
Kaufman
M J
MJ
Munakata
M
M
Hirshman
C
C
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000502:physiology; D006168:Guinea Pigs; D018738:Hexamethonium; D006584:Hexamethonium Compounds / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D006584:Hexamethonium Compounds; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D012702:Serotonin Antagonists; D012701:Serotonin; D018738:Hexamethonium; D001285:Atropine; D011493:Protein Kinase C; D000109:Acetylcholine; D002211:Capsaicin