Oyekan Adebayo O
Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, 77004, USA.
J Pharmacol Exp Ther. 2005 Jun;313(3):1289-95. doi: 10.1124/jpet.104.080218. Epub 2005 Mar 15.
We recently demonstrated that endothelin-1-induced medullary vasodilation despite a potent cortical vasoconstriction in the rat kidney may be accounted for by 20-hydroxyeicosatetraenoic acid (20-HETE) production. This study characterized the effects of 20-HETE and its metabolites, 20-hydroxy prostaglandin E(2) (20-OH PGE(2)) and 20-hydroxy prostaglandin F(2alpha) (20-OH PGF(2alpha)), and the contribution of nitric oxide (NO) and prostanoids to the changes evoked in cortical blood flow (CBF) and medullary blood flow (MBF). We tested the hypothesis that 20-HETE produces qualitatively different regional hemodynamic effects in the kidney with 20-OH PGF(2alpha) or 20-OH PGE(2), accounting for the vasoconstriction or vasodilation, respectively, in the cortex and medulla. Renal intra-arterial infusion of 1, 2.5, 5, and 10 ng/min 20-HETE decreased CBF by 10 +/- 3, 24 +/- 4, 40 +/- 7, and 58 +/- 9 perfusion units (PU), respectively, but increased MBF by 4 +/- 2, 16 +/- 4, 27 +/- 3, and 41 +/- 10 PU, respectively. 20-OH PGF(2alpha) mimics the effects of 20-HETE, as did PGF(2alpha). However, 20-OH PGE(2) increased both CBF and MBF, as did PGE(2). Indomethacin (5 mg/kg) blunted the effects of 20-HETE but not that of 20-OH PGE(2) and 20-OH PGF(2alpha). However, SQ29548 ([1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3[[2-[(phenylamino)carbonyl[hydrazino]methyl]-7-oxabicyclo]2.2.1]hept-2-yl]-5-heptenoic acid) (0.1 mg/kg), a prostaglandin H(2)/thromboxane A(2) receptor antagonist, blunted the cortical and medullary hemodynamic effects elicited by 20-HETE, 20-OH PGE(2), 20-OH PGF(2alpha), and PGF(2alpha) but not PGE(2). N(omega)-L-nitro arginine methyl ester (5 mg/kg), the inhibitor of NO synthase, exacerbated the cortical constrictor effects of 20-HETE and 20-OH PGF(2alpha) without affecting the medullary perfusion produced by 20-HETE or its metabolites. These findings suggest that 20-HETE, through its hydroxyl metabolites, produced differential effects in the kidney. The medullary perfusion appears to be independent of NO.
我们最近证明，尽管大鼠肾脏中内皮素 -1 会引起强烈的皮质血管收缩，但诱导的髓质血管舒张可能是由 20 - 羟基二十碳四烯酸（20 - HETE）的产生所致。本研究表征了 20 - HETE 及其代谢产物 20 - 羟基前列腺素 E₂（20 - OH PGE₂）和 20 - 羟基前列腺素 F₂α（20 - OH PGF₂α）的作用，以及一氧化氮（NO）和前列腺素对皮质血流（CBF）和髓质血流（MBF）变化的贡献。我们检验了这样一个假设，即 20 - HETE 与 20 - OH PGF₂α 或 20 - OH PGE₂ 在肾脏中产生性质不同的局部血流动力学效应，分别导致皮质的血管收缩和髓质的血管舒张。肾动脉内分别以 1、2.5、5 和 10 ng/min 的速率输注 20 - HETE，CBF 分别降低 10 ± 3、24 ± 4、40 ± 7 和 58 ± 9 灌注单位（PU），但 MBF 分别增加 4 ± 2、16 ± 4、27 ± 3 和 41 ± 10 PU。20 - OH PGF₂α 模拟了 20 - HETE 的作用，PGF₂α 也如此。然而，20 - OH PGE₂ 增加了 CBF 和 MBF，PGE₂ 也如此。吲哚美辛（5 mg/kg）减弱了 20 - HETE 的作用，但未减弱 20 - OH PGE₂ 和 20 - OH PGF₂α 的作用。然而，前列腺素 H₂/血栓素 A₂ 受体拮抗剂 SQ29548（[1S - [1α,2α(Z),3α,4α]] - 7 - [3[[2 - [(苯基氨基)羰基[肼基]甲基] - 7 - 氧杂双环]2.2.1]庚 - 2 - 基] - 5 - 庚烯酸）（0.1 mg/kg）减弱了 20 - HETE、20 - OH PGE₂、20 - OH PGF₂α 和 PGF₂α 引起的皮质和髓质血流动力学效应，但未减弱 PGE₂ 的作用。一氧化氮合酶抑制剂 N(ω) - L - 硝基精氨酸甲酯（5 mg/kg）加剧了 20 - HETE 和 20 - OH PGF₂α 的皮质收缩效应，而不影响 20 - HETE 或其代谢产物产生的髓质灌注。这些发现表明，20 - HETE 通过其羟基代谢产物在肾脏中产生了不同的效应。髓质灌注似乎独立于 NO。
