Characterization of P2Y receptors mediating ATP induced relaxation in guinea pig airway smooth muscle: involvement of prostaglandins and K+ channels

Abstract

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 P2Y(2) and P2Y(4) 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 P2Y(4) and P2Y(2) receptors; (2) induces I (K) increment through activation of the delayed rectifier K(+) channels and the high-conductance Ca(2+)-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.

Inhibition of extracellular nucleotides hydrolysis intensifies the allergic bronchospasm. A novel protective role of ectonucleotidases

“…B). A negative control for P2Y 2 receptor with its blocking peptide was already carried out in a previous work (16). With respect to alkaline phosphatase, confocal images showed that activity of this enzyme was minimal in airway epithelium from nonsensitized guinea pigs (Fig.…”

Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm

“…TEA (1-30 mM) did not inhibit androgen-induced relaxation. Because TEA blocks K v and BK Ca, which are the most important K C channels in ASM (Montaño et al 2011), it can be concluded that they do not participate in the androgen-induced relaxation. In addition, the possibility that the b 2 -adrenoceptors are involved in the relaxation to 5a-DHT or DHEA (Bordallo et al 2008, Espinoza et al 2013, as well as the polyamine synthesis in the relaxation induced by 5a-DHT (Bordallo et al 2008), has been eliminated.…”

Adenosine A1 and Prostaglandin E Receptor 3 Receptors Mediate Global Airway Contraction after Local Epithelial Injury

“…High levels of prostanoids in bronchoalveolar lavage fluid and the increased expression of COX-2 in lung tissue have been detected in subjects with asthma (18). PGE 2 is produced by airway epithelial cells (19)(20)(21) and by smooth muscle cells (22)(23)(24)(25), and has been demonstrated to regulate airway caliber (26)(27)(28). There are four subtypes of PGE 2 receptors: EP 1-4 .…”