Kohagura K, Arima S, Endo Y, Chiba Y, Ito O, Abe M, Omata K, Ito S
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University School of Medicine, Sendai, Japan.
Hypertens Res. 2001 Sep;24(5):551-7. doi: 10.1291/hypres.24.551.
Recent studies have demonstrated that cytochrome P450-dependent metabolites of arachidonic acid (CYP450-AA) play important roles in the control of renal vascular resistance (RVR). In the present study, we examined the possible involvement of CYP450-AA in the vasoconstrictor action of angiotensin II (Ang II) on the afferent arterioles (Af-Arts), a vascular segment crucial to the control of RVR. Rabbit Af-Arts were microperfused at 60 mmHg in vitro, and the vasoconstrictor action of Ang II (10(-11)-10(-8) M, added to both the bath and lumen) was examined with or without blocking the activity of CYP450 epoxygenase or hydroxylase. Ang II decreased the luminal diameter of Af-Arts in a dose-dependent manner (34+/-2% of control diameter at 10(-8) M, n=9, p<0.0001). Pretreatment with miconazole, an inhibitor of CYP450 epoxygenase, at 10(-6) M decreased the basal diameter by 14+/-1% (n=6, p<0.01) and augmented the vasoconstrictor action of Ang II (7+/-3% of control diameter at 10(-8) M, p<0.001 vs. without miconazole). This augmentation was abolished by blocking the Ang II type 2 (AT2) receptor with PD 123319 at 10(-7) M. In contrast, pretreatment with 17-octadecynoic acid (17-ODYA, 10(-6) M), which inhibits both epoxygenase and hydroxylase activity, had no effect on the basal diameter but attenuated the vasoconstrictor action of Ang 11(46+/-2% of control diameter at 10(-8) M, p<0.01 vs. without 17-ODYA). Our results demonstrate that in the Af-Art, endogenous CYP450-AA are involved not only in the control of basal tone but also in the action of Ang II. Further, it appears that the CYP450 epoxygenase pathway attenuates Ang II action via AT2 receptors.
近期研究表明，花生四烯酸的细胞色素P450依赖性代谢产物（CYP450-AA）在肾血管阻力（RVR）的调控中发挥重要作用。在本研究中，我们检测了CYP450-AA是否参与血管紧张素II（Ang II）对入球小动脉（Af-Arts）的血管收缩作用，入球小动脉是对RVR调控至关重要的血管段。兔Af-Arts在体外60 mmHg压力下进行微灌注，在有或无阻断CYP450环氧化酶或羟化酶活性的情况下，检测Ang II（10⁻¹¹ - 10⁻⁸ M，添加到浴槽和管腔中）的血管收缩作用。Ang II以剂量依赖性方式降低Af-Arts的管腔直径（在10⁻⁸ M时为对照直径的34±2%，n = 9，p < 0.0001）。用10⁻⁶ M的CYP450环氧化酶抑制剂咪康唑预处理可使基础直径降低14±1%（n = 6，p < 0.01），并增强Ang II的血管收缩作用（在10⁻⁸ M时为对照直径的7±3%，与无咪康唑时相比p < 0.001）。用10⁻⁷ M的PD 123319阻断血管紧张素II 2型（AT2）受体可消除这种增强作用。相反，用17-十八炔酸（17-ODYA，10⁻⁶ M）预处理，该物质可抑制环氧化酶和羟化酶活性，对基础直径无影响，但减弱了Ang II的血管收缩作用（在10⁻⁸ M时为对照直径的46±2%，与无17-ODYA时相比p < 0.01）。我们的结果表明，在Af-Arts中，内源性CYP450-AA不仅参与基础张力的调控，还参与Ang II的作用。此外，似乎CYP450环氧化酶途径通过AT2受体减弱Ang II的作用。
