Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
Vascul Pharmacol. 2012 Jan-Feb;56(1-2):84-90. doi: 10.1016/j.vph.2011.11.005. Epub 2011 Dec 3.
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.
本研究旨在探讨花生四烯酸是否会抑制肺血管中的血管钠钾-ATP 酶，如果是，涉及哪些机制。在使用无钾溶液和 5-HT 收缩的绵羊肺动脉环中，通过钾诱导的松弛来研究功能性钠钾-ATP 酶活性。花生四烯酸（10-100μM）引起浓度依赖性抑制 KCl 诱导的松弛，并增加基础动脉张力。细胞色素 P-450 抑制剂 17-辛炔酸（17-ODYA）完全逆转了花生四烯酸（30μM）诱导的 KCl 松弛抑制。此外，在选择性 20-羟二十碳四烯酸（20-HETE）阻断剂 HET0016 的存在下，花生四烯酸诱导的 KCl 松弛抑制不明显。因此，花生四烯酸的细胞色素 P-450 代谢产物 20-HETE 也显著减弱了 KCl 诱导的松弛。然而，脂氧合酶抑制剂去甲二氢愈创木酸（NDGA）部分恢复了在存在花生四烯酸（30μM）时受损的 K+诱导的松弛。另一方面，环氧化酶抑制剂吲哚美辛未能逆转花生四烯酸对 KCl 诱导的松弛的抑制作用。蛋白激酶 C 抑制剂白屈菜红碱完全逆转了花生四烯酸和 20-HETE 对 K+诱导的松弛的抑制作用。结论表明，20-HETE，花生四烯酸的细胞色素 P-450 代谢物在抑制绵羊肺动脉中功能性钠钾-ATP 酶活性方面起主要作用，而脂氧合酶途径起次要作用。显然，蛋白激酶 C 参与了花生四烯酸/20-HETE 抑制绵羊肺动脉钠钾-ATP 酶的作用。
