title: 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.
authors.affiliation: Departamento de Farmacología, Edificio de Investigación, sexto piso, laboratorio 3, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Mexico, DF, Mexico. lmmr@servidor.unam.mx
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montaño
authors.forename: José E
authors.initials: JE
authors.lastname: Cruz-Valderrama
authors.forename: Alejandra
authors.initials: A
authors.lastname: Figueroa
authors.forename: Edgar
authors.initials: E
authors.lastname: Flores-Soto
authors.forename: Luz M
authors.initials: LM
authors.lastname: García-Hernández
authors.forename: Verónica
authors.initials: V
authors.lastname: Carbajal
authors.forename: Patricia
authors.initials: P
authors.lastname: Segura
authors.forename: Carmen
authors.initials: C
authors.lastname: Méndez
authors.forename: Verónica
authors.initials: V
authors.lastname: Díaz
authors.forename: Carlos
authors.initials: C
authors.lastname: Barajas-López
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate; D000818:Animals; D005033:Ethylmaleimide / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011453:Prostaglandins; D058470:Receptors, Purinergic P2Y / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D014132:Trachea / Q000502:physiology; D014227:Triazines / Q000494:pharmacology
chemical_list: D010455:Peptides; D015221:Potassium Channels; D011453:Prostaglandins; D058470:Receptors, Purinergic P2Y; D014227:Triazines; C017759:9-(tetrahydro-2-furyl)-adenine; C012842:Cibacron Blue F 3GA; D013498:Suramin; C064719:iberiotoxin; D000255:Adenosine Triphosphate; D015761:4-Aminopyridine; D000225:Adenine; D005033:Ethylmaleimide