Receptors and signaling pathway underlying relaxations to isoprostanes in canine and porcine airway smooth muscle.
Using muscle bath techniques, we examined the inhibitory activities of several E- and F-ring isoprostanes in canine and porcine airway smooth muscle. 8-Isoprostaglandin E1 and 8-isoprostaglandin E2 (8-iso PGE2) reversed cholinergic tone in a concentration-dependent manner, whereas the F-ring isoprostanes were ineffective. Desensitization with 8-iso-PGE2 and PGE2 implicated isoprostane activity at the PGE2 receptor (EP). We found that the inhibitory E-ring isoprostane responses were significantly augmented by rolipram (a type IV phosphodiesterase inhibitor), while 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (a guanylate cyclase inhibitor) had no effect, suggesting a role for cAMP in isoprostane-mediated relaxations. 8-Iso-PGE2 did not reverse KCl tone, suggesting that voltage-dependent Ca2+ influx and myosin light chain kinase are not suppressed by isoprostanes. Patch-clamp studies showed marked suppression of K+ currents by 8-iso-PGE2. We conclude that E-ring isoprostanes exert PGE2 receptor-directed, cAMP-dependent relaxations in canine and porcine airway smooth muscle. This activity is not dependent on K+ channel activation or the direct inhibition of voltage-operated Ca2+ influx or myosin light chain kinase.
Catalli
Adriana
A
Asthma Research Group, Father Sean O'Sullivan Research Center, Firestone Institute for Respiratory Health, St. Joseph's Hospital, McMaster University, Hamilton, Ontario, Canada L8N 4A6. janssenl@mcmaster.ca
Zhang
Dawei
D
Janssen
Luke J
LJ
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D066298:In Vitro Techniques; D028421:Isoprostanes / Q000494:pharmacology*; D007700:Kinetics; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D013552:Swine; D014132:Trachea / Q000187:drug effects / Q000502:physiology*
D028421:Isoprostanes; D015232:Dinoprostone; C011987:8-isoprostaglandin E2