Kondo Naoki, Kiyomoto Hideyasu, Yamamoto Tokunori, Miyatake Akira, Sun Guang-Ping, Rahman Matlubur, Hitomi Hirofumi, Moriwaki Kumiko, Hara Taiga, Kimura Shoji, Abe Youichi, Kohno Masakazu, Nishiyama Akira
Second Department of Internal Medicine, Kagawa University Medical School, Kagawa, Japan.
J Pharmacol Exp Ther. 2006 Mar;316(3):1047-52. doi: 10.1124/jpet.105.095331. Epub 2005 Nov 30.
Recent studies have indicated that derangement of peritubular capillary (PTC) circulation with consequent tubulointerstitial hypoxia plays a pivotal role in the pathogenesis of renal injury. The present study was performed to determine whether azelnidipine, a new dihydropyridine calcium channel blocker, attenuates angiotensin II (AngII)-induced peritubular ischemia in anesthetized rats. The superficial PTCs were visualized directly using an intravital fluorescence videomicroscope system, and the PTC blood flow was evaluated by analyzing the velocity of fluorescein isothiocyanate-labeled erythrocytes. Intravenous infusion of AngII (50 ng/kg/min, 10 min) significantly increased mean arterial pressure (MAP) and renal vascular resistance (RVR) (by 35 +/- 3% and 110 +/- 32%, respectively), and decreased total renal blood flow (RBF) and PTC erythrocyte velocity (by -34 +/- 4 and -37 +/- 1%, respectively). Treatment with azelnidipine (5 microg/kg/min i.v., 10 min) had no effect on basal MAP, RBF, RVR, or PTC erythrocyte velocity. However, azelnidipine markedly attenuated the AngII-induced increases in MAP (7 +/- 3%) and RVR (40 +/- 4%) and decreases in RBF (-24 +/- 1%) and PTC erythrocyte velocity (-22 +/- 1%). Similar attenuation in the AngII-induced responses of MAP, RBF, RVR, and PTC erythrocyte velocity were observed in rats treated with a higher dose of azelnidipine (20 microg/kg/min i.v., 10 min), which significantly decreased basal MAP and RVR and increased RBF and PTC erythrocyte velocity. These data suggest that calcium channel blockade attenuates AngII-induced peritubular ischemia, which may be involved in its beneficial effects on renal injury.
近期研究表明，肾小管周围毛细血管（PTC）循环紊乱及随之而来的肾小管间质缺氧在肾损伤发病机制中起关键作用。本研究旨在确定新型二氢吡啶类钙通道阻滞剂阿折地平是否能减轻麻醉大鼠中血管紧张素II（AngII）诱导的肾小管周围缺血。使用活体荧光视频显微镜系统直接观察浅表PTC，并通过分析异硫氰酸荧光素标记红细胞的速度来评估PTC血流。静脉输注AngII（50 ng/kg/min，持续10分钟）显著升高平均动脉压（MAP）和肾血管阻力（RVR）（分别升高35±3%和110±32%），并降低总肾血流量（RBF）和PTC红细胞速度（分别降低-34±4%和-37±1%）。阿折地平（5μg/kg/min静脉注射，持续10分钟）治疗对基础MAP、RBF、RVR或PTC红细胞速度无影响。然而，阿折地平显著减轻了AngII诱导的MAP升高（7±3%）和RVR升高（40±4%）以及RBF降低（-24±1%）和PTC红细胞速度降低（-22±1%）。在用更高剂量阿折地平（20μg/kg/min静脉注射，持续10分钟）治疗的大鼠中，观察到对AngII诱导的MAP、RBF、RVR和PTC红细胞速度反应有类似的减轻作用，该剂量显著降低基础MAP和RVR，并增加RBF和PTC红细胞速度。这些数据表明，钙通道阻滞可减轻AngII诱导的肾小管周围缺血，这可能与其对肾损伤的有益作用有关。
