GLOMERULAR STEREOSPECIFIC SYNTHESIS AND HEMODYNAMIC ACTIONS OF 8,9-EPOXYEICOSATRIENOIC ACID IN RAT-KIDNEY
GLOMERULAR STEREOSPECIFIC SYNTHESIS AND HEMODYNAMIC ACTIONS OF 8,9-EPOXYEICOSATRIENOIC ACID IN RAT-KIDNEY
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DOI：
10.1152/ajprenal.1991.261.4.f578
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发表时间：
1991-10-01
影响因子：
--
通讯作者：
BADR, KF
中科院分区：
文献类型：
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作者：
KATOH, T;TAKAHASHI, K;BADR, KF
内源性花生四烯酸通过细胞色素P-450环氧化酶在肾小球和皮质代谢产生8,9-,11,12-和14,15-环氧二碳三烯酸（EET）。采用气相色谱-质谱联用技术，测定了正常大鼠肾脏内源性花生四烯酸池中8,9- eet的合成。（8S,9R）同分异构体在离体肾小球中比（8R,9S）更受欢迎，在皮质组织中比（68:32）为59比41。（8S,9R）但不(8R,9S)-EET在大鼠肾内给药时引起剂量依赖性血管收缩。肾小球动力学的微穿刺测量显示，(8S,9R)-EET增加传入小动脉阻力（R(A)），导致单肾元血浆流速（Q(A)）、净经毛细血管水压差（DELTA-P）降低，从而降低单肾元肾小球滤过率（SNGFR）。肾小球毛细血管超滤系数（K(f)）值无明显变化。在环加氧酶抑制剂吲哚美辛的存在下，8,9- eet的作用被逆转。R(A)下降导致Q(A)和DELTA-P增加，从而导致SNGFR增加。在这些条件下，注意到K(f)的适度降低。因此，(8S,9R)-EET是一种立体选择性肾血管收缩剂，优先于其光学异构体(8R,9S)-EET产生，这表明它具有生物学相关性，并暗示了EET受体激活的特定结构要求。8,9- eet的主要作用机制是肾小球前血管收缩。8,9- eet的血管收缩作用是CO依赖的。
Renal glomerular and cortical metabolism of endogenous arachidonic acid by cytochrome P-450 epoxygenase yields 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EET). Using gas chromatography-mass spectrometry, we measured the synthesis of 8,9-EET from an endogenous pool of arachidonic acid in normal rat kidney. The (8S,9R) isomer was favored over the (8R,9S) isomer in a ratio (%) of 59 to 41 in isolated glomeruli and 68 to 32 in cortex tissue. (8S,9R)-but not (8R,9S)-EET elicited dose-dependent vasoconstriction on intrarenal administration in the euvolemic Munich-Wistar rat. Micropuncture meaurements of glomerular dynamics revealed that (8S,9R)-EET increased afferent arteriolar resistance (R(A)) leading to reductions in single-nephron plasma flow rate (Q(A)), net transcapillary hydraulic pressure difference (DELTA-P), and consequently single-nephron glomerular filtration rate (SNGFR). There was no significant change in the value of the glomerular capillary ultrafiltration coefficient (K(f)). In the presence of a cyclooxygenase inhibitor, indomethacin, the effects of 8,9-EET were reversed. R(A) fell leading to increases in Q(A) and DELTA-P, with resultant augmentation of SNGFR. Under these conditions, a modest reduction if K(f) was noted. Thus (8S,9R)-EET is a stereoselective renal vasoconstrictor, preferentially generated over its optical isomer, (8R,9S)-EET, suggesting that is is biologically relevant and implying specific structural requirements for EET receptor activation. The principal mechanism of action of 8,9-EET is preglomerular vasoconstriction. The vasoconstrictor effect of 8,9-EET is CO dependent.