Renal cytochrome P450 oxygenases and preglomerular vascular response to arachidonic acid and endothelin-1 following ischemia/reperfusion
Renal cytochrome P450 oxygenases and preglomerular vascular response to arachidonic acid and endothelin-1 following ischemia/reperfusion
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DOI：
10.1124/jpet.302.2.717
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发表时间：
2002-08-01
影响因子：
3.5
通讯作者：
Oyekan, A
中科院分区：
文献类型：
--
作者：
Hercule, H;Oyekan, A
本研究验证了花生四烯酸(AA)的细胞色素P450(P450)代谢产物参与大鼠缺血再灌注(I/R)损伤血管改变的假说。在大鼠左肾I/R后，阻断左肾动静脉30min，再灌流(I/R)3、6、24小时后，肾微体omega-羟基酶介导的[C-14]AA转化为20-羟基二十碳四烯酸(HETE)活性显著降低。细胞色素P4A蛋白表达也降低。环氧合酶活性无明显变化。尽管有这些变化，AA或内皮素-1(ET-1)对大鼠PGMV的收缩作用与夹闭和非夹闭(对侧)肾的血管没有区别。静脉注射氯贝特(250 mg/kg)不增加20-HETE的产生，但选择性地增强AA和ET-1引起的血管收缩，而不影响9，11-二脱氧-9α，11α-甲氧基前列腺素F-2α引起的收缩。另一方面，给予2%氯化钠(w/v，连续7天)诱导依赖P450的环氧合酶活性可减弱AA引起的血管收缩，但增强ET-1引起的血管收缩。这些数据表明，在I/R中，CyP4A蛋白表达和酶活性的降低是保护肾血管免受过度收缩的一种适应性机制。此外，盐负荷后环氧合酶活性的增加可能是AA引起的血管收缩减弱的原因。然而，盐对ET-1诱导的I/R血管收缩的增强作用似乎是由于盐诱导的肾血管对ET-1的增敏作用超过了扩张剂环氧合酶产物的产生。
This study tested the hypothesis that cytochrome P450 (P450) metabolites of arachidonic acid (AA) contribute to the vascular changes in ischemia/reperfusion (I/R) injury in the rat. In this study, P450-dependent omega-hydroxylase-mediated vascular reactivity of the rat renal interlobular and arcuate vessels [pre-glomerular vessels (PGMV)] was measured in left kidneys subjected to I/R. Clipping the left renal artery and vein for 30 min followed by reperfusion (I/R) for 3, 6, and 24 h markedly reduced renal microsomal omega-hydroxylase-mediated conversion of [C-14]AA to 20-hydroxyeicosatetraenoic acid (HETE) that amounted to 34, 37, and 58% of the control enzyme activity, respectively. CYP4A protein expression was also reduced. There was no significant change in epoxygenase activity. Despite these changes, constriction of the rat PGMV by AA or endothelin-1 (ET-1) was not different in vessels from the clipped and nonclipped (contralateral) kidney. Clofibrate (250 mg/kg i.p.), an inducer of CYP4A protein and omega-hydroxylase enzymes, did not increase 20-HETE production but selectively enhanced the vasoconstriction produced by AA and ET-1 in the clipped but not the contralateral kidney without affecting the constriction produced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F-2alpha. On the other hand, administration of 2% NaCl (w/v, orally for 7 days) to induce P450-dependent epoxygenase activity attenuated AA-induced vasoconstriction but enhanced ET-1-induced vasoconstriction only in the clipped kidney. These data indicate that the reduction in CYP4A protein expression and enzyme activity in I/R is an adaptive mechanism to preserve renal vasculature from excessive vasoconstriction. Moreover, the increase in epoxygenase activity following salt loading may account for the diminished vasoconstriction evoked by AA. However, the enhancing effect of salt on ET-1-induced vasoconstriction in I/R appears to result from an overwhelming effect of salt-induced sensitization of the renal vasculature to ET-1 over the enhanced production of dilator epoxygenase products.