Newaz Mohammad A, Oyekan Adebayo O
Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston 77004, USA.
J Cardiovasc Pharmacol. 2002 Jun;39(6):834-41. doi: 10.1097/00005344-200206000-00008.
Administration of glycerol produces acute renal failure (ARF) accompanied by profound vasoconstriction. It was hypothesized that impaired arachidonic acid metabolism may contribute to the vasoconstriction through alteration of renal eicosanoids or endothelin-1 or angiotensin II stimulation of renal oxygenases. Arachidonic acid (5, 10, 25 microg) in the control kidney produced increases in perfusion pressure of 15 +/- 9, 18 +/- 8, and 43 +/- 18 mm Hg, respectively. These responses were increased 1.5-fold in glycerol-induced renal failure (p < 0.01). Indomethacin (10 microM), the cyclooxygenase inhibitor, converted arachidonic acid vasoconstriction to epoxide-mediated vasodilator responses, which were unchanged in ARF. In ARF, 5,8,11,14-eicosatetraynoic acid (10 microM), the all-purpose inhibitor of arachidonic acid metabolism; indomethacin (10 microM), a cyclooxygenase inhibitor; 5,8,11-eicosatriyenoic acid (2.5 microM), the 5- and 12-lipoxygenase inhibitor; or aminobenzotriazole (50 mM), the cytochrome P-450 monooxygenase inhibitor, markedly attenuated arachidonic acid-induced vasoconstriction by 73 +/- 11% (p < 0.01), 89 +/- 1% (p < 0.01), 62 +/- 11% (p < 0.01), and 82 +/- 2% (p < 0.01), respectively. In ARF, angiotensin II-induced vasoconstriction was amplified by 67% (p < 0.01). Eicosatetraynoic acid, eicosatriyenoic acid, and aminobenzotriazole reduced these responses by 33 +/- 6% (p < 0.05), 53 +/- 6% (p < 0.01), and 52 +/- 11% (p < 0.05), respectively. Vasoconstriction by endothelin-1 was unchanged in ARF (24 +/- 17%). However, indomethacin attenuated endothelin-1 vasoconstriction by 41 +/- 11% (p < 0.05), whereas eicosatriyenoic acid and aminobenzotriazole were without effect. These data suggest that the increased renal vascular reactivity in ARF in response to arachidonic acid involves a relatively greater production of cyclooxygenase metabolites than monoxygenase- or lipoxygenase-derived eicosanoid metabolites. Furthermore, increased angiotensin II vasoconstriction is predominantly through lipoxygenase and monoxygenase metabolic pathways, whereas for endothelin-1, increased cyclooxygenase-derived vasoconstrictor metabolites play a significant role in its amplified vasoconstrictor effect in glycerol-induced ARF.
给予甘油会导致急性肾衰竭（ARF）并伴有严重的血管收缩。据推测，花生四烯酸代谢受损可能通过改变肾类二十烷酸或内皮素 -1 或肾氧合酶受血管紧张素 II 刺激而导致血管收缩。对照肾中花生四烯酸（5、10、25微克）分别使灌注压升高15±9、18±8和43±18毫米汞柱。在甘油诱导的肾衰竭中，这些反应增加了1.5倍（p<0.01）。环氧化酶抑制剂吲哚美辛（10微摩尔）将花生四烯酸血管收缩转化为环氧化物介导的血管舒张反应，在ARF中该反应无变化。在ARF中，花生四烯酸代谢的通用抑制剂5,8,11,14 - 二十碳四烯酸（10微摩尔）；环氧化酶抑制剂吲哚美辛（10微摩尔）；5,8,11 - 二十碳三烯酸（2.5微摩尔），5 - 和12 - 脂氧合酶抑制剂；或细胞色素P - 450单加氧酶抑制剂氨基苯并三唑（50毫摩尔），分别使花生四烯酸诱导的血管收缩显著减弱73±11%（p<0.01）、89±1%（p<0.01）、62±11%（p<0.01）和82±2%（p<0.01）。在ARF中，血管紧张素II诱导的血管收缩增强了67%（p<0.01）。二十碳四烯酸、二十碳三烯酸和氨基苯并三唑分别使这些反应降低33±6%（p<0.05）、53±6%（p<0.01）和52±11%（p<0.05）。在ARF中，内皮素 -1引起的血管收缩无变化（24±17%）。然而，吲哚美辛使内皮素 -1血管收缩减弱41±11%（p<0.05），而二十碳三烯酸和氨基苯并三唑则无作用。这些数据表明，ARF中肾血管对花生四烯酸反应性增加涉及环氧化酶代谢产物的产生相对比单加氧酶或脂氧合酶衍生的类二十烷酸代谢产物更多。此外，血管紧张素II血管收缩增强主要通过脂氧合酶和单加氧酶代谢途径，而对于内皮素 -1，环氧化酶衍生的血管收缩代谢产物增加在其甘油诱导的ARF中增强血管收缩作用中起重要作用。
