Characterization of P2Y receptors mediating ATP induced relaxation in guinea pig airway smooth muscle: involvement of prostaglandins and K+ channels
Tóm tắt
In airway smooth muscle (ASM), adenosine 5′-triphosphate (ATP) induces a relaxation associated with prostaglandin production. We explored the role of K+ currents (I
K) in this relaxation. ATP relaxed the ASM, and this effect was abolished by indomethacin. Removal of airway epithelium slightly diminished the ATP-induced relaxation at lower concentration without modifying the responses to ATP at higher concentrations. ATPγS and UTP induced a concentration-dependent relaxation similar to ATP; α,β-methylene-ATP was inactive from 1 to 100 μM. Suramin or reactive blue 2 (RB2), P2Y receptor antagonists, did not modify the relaxation, but their combination significantly reduced this effect of ATP. The relaxation was also inhibited by N-ethylmaleimide (NEM; which uncouples G proteins). In myocytes, the ATP-induced I
K increment was not modified by suramin or RB2 but the combination of both drugs abolished it. This increment in the I
K was also completely nullified by NEM and SQ 22,536. 4-Amynopyridine or iberiotoxin diminished the ATP-induced I
K increment, and the combination of both substances diminished ATP-induced relaxation. The presence of P2Y2 and P2Y4 receptors in smooth muscle was corroborated by Western blot and confocal images. In conclusion, ATP: (1) produces relaxation by inducing the production of bronchodilator prostaglandins in airway smooth muscle, most likely by acting on P2Y4 and P2Y2 receptors; (2) induces I
K increment through activation of the delayed rectifier K+ channels and the high-conductance Ca2+-dependent K+ channels, therefore both channels are implicated in the ATP-induced relaxation; and (3) this I
K increment is mediated by prostaglandin production which in turns increase cAMP signaling pathway.
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