Exaggerated response to adenosine in kidneys from high salt-fed rats: role of epoxyeicosatrienoic acids
Exaggerated response to adenosine in kidneys from high salt-fed rats: role of epoxyeicosatrienoic acids
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DOI：
10.1152/ajprenal.00421.2004
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发表时间：
2005-08-01
影响因子：
4.2
通讯作者：
Carroll, MA
中科院分区：
文献类型：
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作者：
Liclican, EL;McGiff, JC;Carroll, MA
当腺苷 (2A) 受体 (A(2A)R) 受到刺激时，细胞色素 P-450 (CYP) 依赖性环氧二十碳三烯酸 (EET) 会扩张大鼠肾小球前微血管。由于高盐 (HS) 摄入量会增加环氧化酶活性和腺苷水平，我们推测喂食 HS 的大鼠的肾脏腺苷反应会更大。雄性 Sprague-Dawley 大鼠喂食 HS (4.0% NaCl) 或正常盐 (NS; 0.4% NaCl) 饮食。第8天，用含有吲哚美辛(10μM)和L-NAME(200μM)的Krebs'缓冲液灌注分离的肾脏，并通过输注去氧肾上腺素(10(-7)M)预收缩至类似于150mmHg。提取肾流出物，通过气相色谱-质谱法分析类二十烷酸。稳定的腺苷类似物 2-氯腺苷（2-CA；0.1-10 μg）的快速浓注会导致剂量依赖性扩张；与 NS 大鼠相比，10 μg 剂量下，HS 大鼠肾脏的灌注压 (PP) 降低程度更大（-60 +/- 4 对比 -31 +/- 8 mmHg；P < 0.05），并且反应面积增加（27 +/- 6 对比 9 +/- 4 mm(2)；P < 0.05），EET 释放也增加（132 +/- 23 对比 38）。 +/- 18 纳克；P < 0.05)。 HS 处理增加了 A(2A)R 和 CYP2C23 蛋白表达。选择性环氧化酶抑制剂 MS-PPOH (12 μM) 显着降低 HS 大鼠对 2-CA 的反应； PP、反应面积和 EET 释放分别减少了 40%、70% 和 81%，而 NS 肾脏中的变化较小。因此，在 HS 喂养的大鼠肾脏中观察到的对 2-CA 的更大的血管舒张反应是由 EET 释放增加介导的。由于 EET 是肾血管扩张剂和利钠排泄类二十烷酸，腺苷和 EET 之间的相互作用可能有助于对 HS 摄入的适应性反应。
Cytochrome P-450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) dilate rat preglomerular microvessels when adenosine(2A) receptors (A(2A)R) are stimulated. As high salt (HS) intake increases epoxygenase activity and adenosine levels, we hypothesized that renal adenosine responses would be greater in HS-fed rats. Male Sprague-Dawley rats were fed either HS (4.0% NaCl) or normal salt (NS; 0.4% NaCl) diet. On day 8, isolated kidneys were perfused with Krebs' buffer containing indomethacin (10 mu M) and L-NAME (200 mu M) and preconstricted to similar to 150 mmHg with infusion of phenylephrine (10(-7) M). Renal effluents were extracted for analysis of eicosanoids by gas chromatography-mass spectrometry. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1-10 mu g) resulted in dose-dependent dilation; at 10 mu g, perfusion pressure (PP) was lowered to a greater extent in the kidneys of HS rats compared with NS rats (-60 +/- 4 vs. -31 +/- 8 mmHg; P < 0.05) and the area of response was increased (27 +/- 6 vs. 9 +/- 4 mm(2); P < 0.05), as was EET release (132 +/- 23 vs. 38 +/- 18 ng; P < 0.05). HS treatment increased A(2A)R and CYP2C23 protein expression. A selective epoxygenase inhibitor, MS-PPOH (12 mu M), significantly reduced the response to 2-CA in HS rats; PP, area of response, and EET release decreased by 40, 70, and 81%, respectively, whereas lesser changes were evident in NS kidneys. Thus the greater vasodilator response to 2-CA seen in kidneys obtained from HS-fed rats was mediated by increased EET release. As EETs are renal vasodilator and natriuretic eicosanoids, interactions between adenosine and EETs may contribute to the adaptive response to HS intake.