Airway smooth muscle relaxation induced by 5-HT2A receptors: Role of Na+/K+-ATPase pump and Ca2+-activated K+ channels

AimsAlthough 5-hydroxytryptamine (5-HT) contracts airway smooth muscle in many mammalian species, in guinea pig and human airways 5-HT causes a contraction followed by relaxation. This study explored potential mechanisms involved in the relaxation induced by 5-HT.Main methodsUsing organ baths, patch clamp, and intracellular Ca2+ measurement techniques, the effect of 5-HT on guinea pig airway smooth muscle was studied.Key findingsA wide range of 5-HT concentrations caused a biphasic response of tracheal rings. Response to 32 μM 5-HT was notably reduced by either tropisetron or methiothepin, and almost abolished by their combination. Incubation with 10 nM ketanserin significantly prevented the relaxing phase. Likewise, incubation with 100 nM charybdotoxin or 320 nM iberiotoxin and at less extent with 10 μM ouabain caused a significant reduction of the relaxing phase induced by 5-HT. Propranolol, L-NAME and 5-HT1A, 5-HT1B/5-HT1D and 5-HT2B receptors antagonist did not modify this relaxation. Tracheas from sensitized animals displayed reduced relaxation as compared with controls. In tracheas precontracted with histamine, a concentration response curve to 5-HT (32, 100 and 320 μM) induced relaxation and this effect was abolished by charybdotoxin, iberiotoxin or ketanserin. In single myocytes, 5-HT in the presence of 3 mM 4-AP notably increased the K+ currents (IK(Ca)), and they were completely abolished by charybdotoxin, iberiotoxin or ketanserin.SignificanceDuring the relaxation induced by 5-HT two major mechanisms seem to be involved: stimulation of the Na+/K+-ATPase pump, and increasing activity of the high-conductance Ca2+-activated K+ channels, probably via 5-HT2A receptors.