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N型和L型钙通道拮抗剂可改善肾小球动力学,逆转严重肾硬化,并抑制L-NAME/自发性高血压大鼠模型中的细胞凋亡和增殖。

N- and L-type calcium channel antagonist improves glomerular dynamics, reverses severe nephrosclerosis, and inhibits apoptosis and proliferation in an l-NAME/SHR model.

作者信息

Zhou Xiaoyan, Ono Hidehiko, Ono Yuko, Frohlich Edward D

机构信息

Hypertension Research Laboratories, Ochsner Clinic Foundation, New Orleans, LA 70121, USA.

出版信息

J Hypertens. 2002 May;20(5):993-1000. doi: 10.1097/00004872-200205000-00035.

Abstract

OBJECTIVE

To determine the responses of the new dihydropyridine N- and L-type calcium antagonist, cilnidipine, on systemic and renal hemodynamics, glomerular dynamics, renal function, and histopathology in an Nomega-nitro-l-arginine methylester spontaneously hypertensive rat (l-NAME/SHR) model of nephrosclerosis.

METHODS

Five groups of 20-week-old male SHR were studied using renal micropuncture techniques and histopathological analyses: group 1, control; group 2, cilnidipine (10 mg/kg per day) by gavage, for 3 weeks; group 3, l-NAME (50 mg/l) in drinking water, for 3 weeks; group 4, combination of l-NAME and cilnidipine, for 3 weeks; group 5, l-NAME for 3 weeks, followed by cilnidipine for a subsequent 3 weeks.

RESULTS

Cilnidipine significantly reduced mean arterial pressure, total peripheral resistance and renal vascular resistance, while increasing effective renal blood flow and glomerular filtration rate (P < 0.01) in l-NAME/SHR. These hemodynamic changes were associated with significantly increased single nephron glomerular filtration rate (SNGFR) and plasma flow (SNPF) and decreased afferent glomerular arteriolar resistances when cilnidipine was used alone, and with increased SNGFR and SNPF, but decreased glomerular capillary pressure, afferent and efferent arteriolar resistances, urinary protein excretion, serum creatinine and uric acid concentrations (at least P < 0.05) in l-NAME-exacerbated SHR nephrosclerosis. In addition, glomerular and arteriolar injuries were markedly reversed (both P < 0.01), and glomerular apoptosis and cellular proliferation were inhibited and associated with glomerular tuft enlargement and an increase in cell number.

CONCLUSION

Cilnidipine not only prevented, but reversed, the severe renal hemodynamic and glomerular dynamic changes, including apoptosis and glomerular cellular proliferation, in l-NAME/SHR-exacerbated nephrosclerosis. This dual-channel calcium antagonist thus exerted renoprotective pathophysiological effects in the l-NAME/SHR.

摘要

目的

在N-硝基-L-精氨酸甲酯自发性高血压大鼠(l-NAME/SHR)肾硬化模型中,确定新型二氢吡啶N型和L型钙拮抗剂西尼地平对全身和肾脏血流动力学、肾小球动力学、肾功能及组织病理学的影响。

方法

采用肾脏微穿刺技术和组织病理学分析方法,对5组20周龄雄性SHR进行研究:第1组为对照组;第2组通过灌胃给予西尼地平(每天10 mg/kg),持续3周;第3组饮用含l-NAME(50 mg/l)的水,持续3周;第4组为l-NAME与西尼地平联合用药,持续3周;第5组先给予l-NAME 3周,随后给予西尼地平3周。

结果

在l-NAME/SHR中,西尼地平显著降低平均动脉压、总外周阻力和肾血管阻力,同时增加有效肾血流量和肾小球滤过率(P<0.01)。单独使用西尼地平时,这些血流动力学变化与单个肾单位肾小球滤过率(SNGFR)和血浆流量(SNPF)显著增加以及入球小动脉阻力降低有关;在l-NAME加重的SHR肾硬化中,与SNGFR和SNPF增加、肾小球毛细血管压力降低、入球和出球小动脉阻力降低、尿蛋白排泄、血清肌酐和尿酸浓度降低(至少P<0.05)有关。此外,肾小球和小动脉损伤明显减轻(均为P<0.01),肾小球凋亡和细胞增殖受到抑制,并与肾小球毛细血管丛增大和细胞数量增加有关。

结论

西尼地平不仅预防而且逆转了l-NAME/SHR加重的肾硬化中严重的肾脏血流动力学和肾小球动力学变化,包括凋亡和肾小球细胞增殖。因此,这种双通道钙拮抗剂在l-NAME/SHR中发挥了肾脏保护的病理生理作用。

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