Arachidonic acid relaxes human pulmonary arteries through K+ channels and nitric oxide pathways.
We aimed to investigate the role of K(+) channels and nitric oxide (NO) on the relaxant effects of arachidonic acid in the human intralobar pulmonary arteries. Arachidonic acid produced a concentration-dependent relaxation (E(max)=93+/-3% of maximal relaxation induced by papaverine 0.1 mM;-log EC(30)=7.03+/-0.09) that was antagonized by the cyclooxygenase inhibitor indomethacin (1 microM), by the combination of cyclooxygenase blockade and cytochrome P450 (CYP) blockade with 17-octadecynoic acid (17-ODYA, 10 microM), by the combination of cyclooxygenase inhibition and NO synthase (NOS) inhibition with N(omega)-nitro-l-arginine (l-NOARG, 100 microM), by the simultaneous inhibition of CYP and NOS and by the simultaneous blockade of cyclooxygenase, CYP and NOS. Arachidonic acid-induced relaxation was significantly inhibited by glibenclamide (1 microM, ATP-dependent K(+) channel (K(ATP)) blocker), apamin and charybdotoxin (0.3 microM small (SK(Ca)) and 0.1 microM big (BK(Ca)) conductance Ca(2+)-sensitive K(+) channel blocker, respectively), and 4-aminopyridine (1 mM, voltage-dependent K(+) channel (K(V)) blocker). Indomethacin and ketoconazole suppressed the antagonistic effects of glibenclamide and apamin and 17-ODYA those of all the K(+) channel blockers tested. l-NOARG suppressed only the antagonistic effect of glibenclamide. We suggest that K(ATP), SK(Ca), BK(Ca) and K(V) are involved in the arachidonic acid-induced relaxation of human pulmonary arteries. Cyclooxygenase metabolites are the main relaxing agents of arachidonic acid, involving K(ATP) and SK(Ca) channels. CYP-dependent metabolites modulate arachidonic acid-induced relaxation through a pathway involving K(+) channels. K(ATP) channels are involved through a NOS-dependent pathway.
Guerard
Pascal
P
Laboratory of Cardiovascular Physiopathology and Pharmacology, Faculty of Medicine, 7 bd. Jeanne d'Arc, BP 87900, 21079 Dijon cedex, France. Pascal.Guerard@u-bourgogne.fr
Goirand
Françoise
F
Fichet
Nicolas
N
Bernard
Alain
A
Rochette
Luc
L
Morcillo
Esteban J
EJ
Dumas
Monique
M
Bardou
Marc
M
D016718:Arachidonic Acid / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D015221:Potassium Channels; D016718:Arachidonic Acid; D009569:Nitric Oxide