Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension
Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension
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DOI：
10.1152/ajpregu.1999.276.3.r766
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发表时间：
1999-03-01
影响因子：
2.8
通讯作者：
McGiff, JC
中科院分区：
文献类型：
--
作者：
Oyekan, AO;McAward, K;McGiff, JC
在单侧肾切除（UNx）大鼠中，用氯化钴（CoCl 2）抑制细胞色素P-450（CYP 450）酶可预防DOCA和盐（1% NaCl）诱导的高血压、器官肥大和肾损伤。通过粘土21，收缩压（SBP）从DOCA-盐治疗的对照水平150 +/- 7 mmHg升至193 +/- 6 mmHg，CoCl 2阻止了该升高（24 mg.kg（-1. 24 h（-1））。DOCA-盐处理的影响，即蛋白质排泄从第3天的9.0 +/- 1.1 mg/24 h增加到第21天的88.3 +/- 6.9 mg/24 h，被CoCl 2阻止。CoCl 2还可减轻高血压大鼠肾脏和左心室肥厚以及中膜/管腔比的增加。DOCA-盐治疗使内皮素（ET）-1的排泄量从81 +/- 17增加到277 +/- 104 pg/100 g体重（-1. 24 h（-1）），相关的20-羟基二十碳四烯酸（20-HETE）排泄量增加4倍，从3.0 +/- 1.1增加到12.2 +/- 1.9 ng/100 g体重（-1. 24 h（-1））（第3天对第21天）。氯化钴分别使这些增加减弱了58%和72%。在[H-3]胸苷脉冲的主动脉环中，ET-1增加其掺入。20-HETE合成抑制剂Dibromodododec-11-enoic acid减弱ET-1诱导的[H-3]胸苷掺入增加。我们通过用1-氨基苯并三唑（ABT）治疗UNx-盐-DOCA大鼠（抑制CYP 450酶活性），区分了CoCl 2通过CO生成与抑制CYP 450-花生四烯酸代谢发挥作用的效果，并将这些结果与CoCl 2产生的结果进行了比较。ABT降低了高血压，CoCl 2也是如此。与CoCl 2不同，ABT不能防止器官肥大和蛋白尿，这表明这些作用部分与CO形成有关。BMS-182874阻断ETA受体可降低SEP、器官肥大和蛋白尿，表明ET引发的异常对UNx-盐-DOCA中病变进展的重要性。
Inhibition of cytochrome P-450 (CYP450) enzymes with cobalt chloride (CoCl2) prevented hypertension, organ hypertrophy, and renal injury induced by DOCA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic blood pressure (SBP) rose to 193 +/- 6 mmHg by clay 21 from control levels of 150 +/- 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by CoCl2 (24 mg.kg(-1).24 h(-1)). The effects of DOCA-salt treatment, which increased protein excretion to 88.3 +/- 6.9 mg/24 h on day 21 from 9.0 +/- 1.1 mg/24 h on day 3, were prevented by CoCl2. CoCl2 also attenuated the renal and left ventricular hypertrophy and the increase in media-to-lumen ratio in hypertensive rats. DOCA-salt treatment increased excretion of endothelin (ET)-1 from 81 +/- 17 to 277 +/- 104 pg.100 g body wt(-1).24 h(-1) associated with a fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE) excretion from 3.0 +/- 1.1 to 12.2 +/- 1.9 ng 100 g body wt(-1).24 h(-1) (days 3 vs. 21). CoCl2 blunted these increases by 58 and 72%, respectively. In aortic rings pulsed with [H-3]thymidine, ET-1 increased its incorporation. Dibromododec-11-enoic acid, an inhibitor of 20-HETE synthesis, attenuated ET-1-induced increases in [H-3]thymidine incorporation. We distinguished effects of CoCl2 acting via CO generation vs. suppression of CYP450-arachidonic acid metabolism by treating UNx-salt-DOCA rats with 1-aminobenzotriazole (ABT), which suppresses CYP450 enzyme activity, and compared these results to those produced by CoCl2. ABT reduced hypertension, as did CoCl2. Unlike CoCl2, ABT did not prevent organ hypertrophy and proteinuria, suggesting that these effects were partially related to CO formation. Blockade of the ETA receptor with BMS-182874 reduced SEP, organ hypertrophy, and proteinuria, indicating the importance of ET-initiated abnormalities to the progression of lesions in UNx-salt-DOCA.