Gebremedhin D, Ma Y H, Imig J D, Harder D R, Roman R J
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226.
J Vasc Res. 1993 Jan-Feb;30(1):53-60. doi: 10.1159/000158975.
The contribution of cytochrome P-450 metabolites of arachidonic acid in elevating vascular tone in the kidneys of adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was examined using a juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. At 80 mm Hg, the basal internal diameters of arcuate and interlobular arteries and proximal and distal afferent arterioles of the SHR averaged 341 +/- 15.81 +/- 5.24 +/- 0.5 and 19 +/- 0.3 micron, respectively. These diameters were 5-29% smaller (p < 0.05) than those measured in corresponding vessels in WKY rats. Addition of the P-450 inhibitors, ketoconazole (100 microM) or 17-octadecynoic acid (17-ODYA, 20 microM), to the perfusate and bath increased the diameters of the preglomerular vasculature of the SHR by 6-29%, but by only 3-13% in WKY rats and reduced significantly the differences in pressure-diameter relations between the two groups. The rate of formation of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical microsomes was similar in SHR and WKY rats. However, the production of epoxyeicosatrienoic acids (EETs) by cortical microsomes was 87% lower and dihydroxyeicosatrienoic acids (DHETs) 70% higher in the SHR than WKY rats. Ketoconazole (100 microM) reduced the formation of 20-HETE by 80%, and EETs and DHETs production by more than 98% in SHR and WKY rats. 17-ODYA (20 microM) reduced the formation of 20-HETE, EETs and DHETs by more than 98% in both groups. These results suggest that cytochrome P-450 metabolites of arachidonic acid contribute to the elevated renal vascular tone in adult SHR. This may be due to an enhanced vascular responsiveness to vasoconstrictor P-450 metabolites in SHR or an elevated local production of vasoconstrictor eicosanoids in the renal vasculature of SHR rather than in renal cortical tissue.
采用含有5%白蛋白的生理盐溶液对成年自发性高血压大鼠（SHR）和Wistar-Kyoto（WKY）大鼠肾脏的近髓肾单位微血管标本进行体外灌注，研究花生四烯酸的细胞色素P-450代谢产物对升高血管张力的作用。在80 mmHg时，SHR的弓形动脉、小叶间动脉、近端和远端传入小动脉的基础内径平均分别为341±15.8、15.8±5.2、5.2±0.5和19±0.3微米。这些内径比WKY大鼠相应血管的测量值小5%-29%（p<0.05）。向灌注液和浴液中添加P-450抑制剂酮康唑（100 microM）或17-十八碳炔酸（17-ODYA，20 microM），可使SHR的球前血管系统内径增加6%-29%，但在WKY大鼠中仅增加3%-13%，并显著缩小两组之间压力-直径关系的差异。SHR和WKY大鼠肾皮质微粒体形成20-羟基二十碳四烯酸（20-HETE）的速率相似。然而，SHR肾皮质微粒体产生的环氧二十碳三烯酸（EETs）比WKY大鼠低87%，二羟基二十碳三烯酸（DHETs）比WKY大鼠高70%。酮康唑（100 microM）使SHR和WKY大鼠中20-HETE的形成减少80%，EETs和DHETs的产生减少98%以上。17-ODYA（20 microM）使两组中20-HETE、EETs和DHETs的形成减少98%以上。这些结果表明，花生四烯酸的细胞色素P-450代谢产物导致成年SHR肾血管张力升高。这可能是由于SHR对血管收缩性P-450代谢产物的血管反应性增强，或者是SHR肾血管系统中血管收缩性类花生酸的局部产生增加，而不是肾皮质组织中增加。
