title: Arachidonic acid inhibits Na⁺-K⁺-ATPase via cytochrome P-450, lipoxygenase and protein kinase C-dependent pathways in sheep pulmonary artery.
abstract: The purpose of the study was to examine whether arachidonic acid inhibits vascular Na(+)-K(+)-ATPase in pulmonary vasculature and if so, what are the mechanisms involved. Functional Na(+)-K(+)-ATPase activity was studied in terms of K(+)-induced relaxation in sheep pulmonary arterial rings contracted with K(+)-free solution and 5-HT. Arachidonic acid (10-100 μM) caused concentration-dependent inhibition of KCl-induced relaxations and also increased basal arterial tone. Cytochrome P-450 inhibitor, 17-octadecynoic acid (17-ODYA) completely reversed the arachidonic acid (30 μM)-induced inhibition of KCl relaxation. Further, in the presence of HET0016, a selective blocker of 20-hydroxyeicosatetraenoic acid (20-HETE), arachidonic acid-induced inhibition of KCl relaxation was not evident. Accordingly, 20-HETE, a cytochrome P-450 metabolite of arachidonic acid, also significantly attenuated KCl-induced relaxations. Norhydihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, however, partially restored the relaxation to K(+), impaired in the presence of arachidonic acid (30 μM). On the other hand, cyclooxygenase inhibitor indomethacin failed to reverse the inhibitory effect of arachidonic acid on KCl-induced relaxation. Staurosporin, a protein kinase C inhibitor, completely reversed the inhibitory effect of arachidonic acid and 20-HETE on K(+)-induced relaxation. In conclusion, the results suggest that 20-HETE, a cytochrome P-450 metabolite of arachidonic acid has a predominant role in the inhibition of functional Na(+)-K(+)-ATPase activity in the sheep pulmonary artery, while the lipooxygenase pathway has a secondary role. It is also evident that protein kinase C is involved in the inhibition of Na(+)-K(+)-ATPase by arachidonic acid/20-HETE in sheep pulmonary artery.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India. tusingh80@gmail.com
authors.forename: Thakur Uttam
authors.initials: TU
authors.lastname: Singh
authors.forename: Soumen
authors.initials: S
authors.lastname: Choudhury
authors.forename: Subhashree
authors.initials: S
authors.lastname: Parida
authors.forename: Bhojane Somnath
authors.initials: BS
authors.lastname: Maruti
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008297:Male; D011188:Potassium / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; D012701:Serotonin; C047008:17-octadecynoic acid; D011189:Potassium Chloride; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D019311:Staurosporine; D011188:Potassium; D007213:Indomethacin