Division of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan.
J Hypertens. 2012 Aug;30(8):1620-31. doi: 10.1097/HJH.0b013e3283550e9f.
Blockade of the T-type calcium channel (TCC), which is expressed in the renal efferent arterioles of the juxtamedullary nephron and vasa recta, has been shown to protect against renal injury. Studies were designed to determine the effects of a specific TCC blocker, R(-) efonidipine [R(-)EFO], on the regulation of renal circulation.
Renal medullary blood flux (MBF) and cortical blood flux (CBF) were simultaneously monitored using laser-Doppler flowmetry in Sprague-Dawley rats. Responses were also determined in rats with angiotensin II (AngII) induced renal ischemia. Intravenous (i.v.) or renal interstitial (r.i.) infusion of R(-)EFO (0.25 mg/h, i.v. or r.i.) significantly increased MBF by 24.0 ± 7.0 and 21.0 ± 4.4%, respectively, but without changing CBF or mean arterial pressure. The nitric oxide (NO) synthase inhibitor NG-nitro-L-argininemethylester (L-NAME, 1 μg/kg per min, i.v. or r.i.) significantly attenuated R(-)EFO-induced increase in MBF. R(-)EFO inhibited the AngII-mediated (50 ng/kg per min, i.v.) reduction of MBF (28.4 ± 1.7%), which was associated with increased urinary NO(2) + NO(3) excretion and decreased urinary hydrogen peroxide (H(2)O(2)) excretion. Intracellular H(2)O(2) fluorescence (real-time fluorescence imaging) in the epithelial cells of isolated medullary thick ascending limb (mTAL) significantly increased following AngII stimulation (1 μmol/L, 235 ± 52 units), which was significantly inhibited by pre and coincubation with R(-)EFO. R(-)EFO stimulation also increased the intracellular NO concentration in the epithelial cells of mTAL (220 ± 62 units).
These results suggest that TCC blockade with R(-)EFO selectively increases MBF, an effect that appears to be mediated by changes in renal NO and oxidative stress balance, which may protect against ischemic renal injury in the renal medullary region.
阻断 T 型钙通道（TCC）可保护肾脏免受损伤，该通道在近髓质肾单位的出球小动脉和直小血管中表达。本研究旨在探讨一种 TCC 阻断剂 R(-)efonidipine[R(-)EFO]对肾循环调节的影响。
使用激光多普勒血流仪同时监测 Sprague-Dawley 大鼠的肾髓质血流（MBF）和皮质血流（CBF）。还在血管紧张素 II（AngII）诱导的肾缺血大鼠中确定了反应。静脉内（i.v.）或肾间质（r.i.）输注 R(-)EFO（0.25mg/h，i.v.或 r.i.）分别使 MBF 增加 24.0±7.0%和 21.0±4.4%，但不改变 CBF 或平均动脉压。一氧化氮（NO）合酶抑制剂 NG-硝基-L-精氨酸甲酯（L-NAME，1μg/kg/min，i.v.或 r.i.）显著减弱了 R(-)EFO 引起的 MBF 增加。R(-)EFO 抑制 AngII 介导的 MBF 降低（50ng/kg/min，i.v.）（28.4±1.7%），这与尿 NO2-+NO3-排泄增加和尿过氧化氢（H2O2）排泄减少有关。在分离的髓质升支粗段（mTAL）上皮细胞中，AngII 刺激后细胞内 H2O2 荧光（实时荧光成像）显著增加（1μmol/L，235±52 单位），R(-)EFO 的预孵育和共孵育显著抑制了这一增加。R(-)EFO 刺激也增加了 mTAL 上皮细胞中的细胞内 NO 浓度（220±62 单位）。
这些结果表明，用 R(-)EFO 阻断 TCC 选择性地增加 MBF，这种作用似乎是通过改变肾内 NO 和氧化应激平衡来介导的，这可能有助于防止肾髓质区域的缺血性肾损伤。
