Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites.
Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites.
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P-450 代谢物可改变缺氧性肺血管收缩作用。
DOI：
10.1152/ajpheart.2000.279.4.h1526
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Jacobs,ER
中科院分区：
文献类型：
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作者：
Zhu,D;Birks,EK;Dawson,CA;Patel,M;Falck,JR;Presberg,K;Roman,RJ;Jacobs,ER
20-羟基二糖四烯酸（20-HETE）是花生四烯酸（AA）在人和兔肺微粒体中的细胞色素-450 4A （CYP4A）代谢物，是离体人肺动脉（PA）的扩张剂。然而，关于p -450代谢物对肺血管张力的贡献知之甚少。我们研究了1)两种机制不同的ω-和ω- 1-羟化酶抑制剂对常氧或低氧气体通气兔离体肺灌注压力的影响，2)20-HETE或ω-和ω- 1-羟化酶抑制剂引起兔PA铃声的变化，以及3)肺组织中CYP4A蛋白的表达。在低氧通气时，观察到孤立灌注肺的灌注压适度升高（比常压高55±11%）（FiO2= 0.05）。20-HETE合成抑制剂17-氧癸酸（17-ODYA）或n -甲基磺酰基-12,12-二溴十二烷-11-氨基酰胺（DDMS）使基线灌注压高于对照，缺氧引起的灌注压增加分别比基线压增加92±11%和105±11%。20-HETE放松苯肾上腺素(PE)-收缩PA环。17-ODYA增强了PE诱导的PA环收缩，这与一种促进动脉舒张的产物的抑制作用一致，而6-（20-丙炔氧基苯基）己酸（PPOH），一种环氧化酶抑制剂，减弱了PE的收缩。17-ODYA、DDMS和缺氧阻断AA向20-HETE的转化。CYP4A免疫特异性蛋白证实了CYP4A在雄性兔肺组织中的表达。我们的数据表明，内源性产生的20-HETE可以改变兔肺血管张力，特别是在缺氧条件下。
20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochromeP-450 4A (CYP4A) metabolite of arachidonic acid (AA) in human and rabbit lung microsomes and is a dilator of isolated human pulmonary arteries (PA). However, little is known regarding the contribution ofP-450 metabolites to pulmonary vascular tone. We examined1) the effect of two mechanistically distinct ω- and ω1-hydroxylase inhibitors on perfusion pressures in isolated rabbit lungs ventilated with normoxic or hypoxic gases,2) changes in rabbit PA ring tone elicited by 20-HETE or ω- and ω1-hydroxylase inhibitors, and3) expression of CYP4A protein in lung tissue. A modest increase in perfusion pressure (55 ± 11% above normoxic conditions) was observed in isolated perfused lungs during ventilation with hypoxic gas (FiO2= 0.05). Inhibitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) orN-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline perfusion pressure above that of vehicle and amplified hypoxia-induced increases in perfusion pressures by 92 ± 11% and 105 ± 11% over baseline pressures, respectively. 20-HETE relaxed phenylephrine (PE)-constricted PA rings. Treatment with 17-ODYA enhanced PE-induced contraction of PA rings, consistent with inhibition of a product that promotes arterial relaxation, whereas 6-(20-propargyloxyphenyl)hexanoic acid (PPOH), an epoxygenase inhibitor, blunted contraction to PE. Conversion of AA into 20-HETE was blocked by 17-ODYA, DDMS, and hypoxia. CYP4A immunospecific protein confirms expression of CYP4A in male rabbit lung tissue. Our data suggest that endogenously produced 20-HETE could modify rabbit pulmonary vascular tone, particularly under hypoxic conditions.