Arachidonic acid relaxes human pulmonary arteries through K + channels and nitric oxide pathways

Abstract

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 μM), by the combination of cyclooxygenase blockade and cytochrome P450 (CYP) blockade with 17-octadecynoic acid (17-ODYA, 10 μM), by the combination of cyclooxygenase inhibition and NO synthase (NOS) inhibition with N ω-nitro- l-arginine ( l-NOARG, 100 μM), 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 μM, ATP-dependent K + channel (K ATP) blocker), apamin and charybdotoxin (0.3 μM small (SK Ca) and 0.1 μM 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.