Novartis Institutes for Biomedical Research, Bldg. 437, Rm. 3317, One Health Plaza, East Hanover, NJ 07936.
Am J Physiol Renal Physiol. 2013 Dec 1;305(11):F1593-602. doi: 10.1152/ajprenal.00655.2012. Epub 2013 Aug 7.
The aims of this study were to 1) determine whether renal localization of aliskiren and its antihypertensive and renoprotective effects persist after administration of the drug is stopped and 2) define the renal localization of aliskiren by light microscopy autoradiography. Hypertensive double transgenic rats (dTGR) overexpressing genes for human renin and angiotensinogen were treated with aliskiren (3 mg·kg(-1)·day(-1) sc; osmotic minipumps) or enalapril (18 mg/l in drinking water). After a 2-wk treatment, dTGR were assigned to either continued treatment with aliskiren ("continued"), or to cessation of their respective treatment ("stopped") for a 3-wk washout. One week of treatment with aliskiren and enalapril reduced blood pressure and albuminuria vs. baseline. After cessation of either treatment, blood pressure had returned to pretreatment levels and albuminuria remained relatively low for 1 wk, but rose thereafter similarly in both groups. In contrast, renal mRNA for transforming growth factor-β and renal collagen IV was reduced by aliskiren (continued and stopped groups), but not after cessation of enalapril. Similar patterns were found for collagen IV protein expression. Even 3 wk after stopping aliskiren treatment, renal levels of the drug exceeded its IC50, whereas enalaprilat was not detected. To localize aliskiren accumulation, Wistar rats were treated with [(3)H]-aliskiren for 7 days. Autoradiography demonstrated specific labeling in glomeruli, arterioles, and afferent arterioles as well as in the distal nephron. Labeling could still be observed even after 7 days' washout. These results suggest that the renophilic properties of aliskiren are different from enalapril and could have contributed to the renoprotective mechanism of this renin inhibitor.
1）确定在停止给予药物后，阿利吉仑的肾脏定位及其降压和肾脏保护作用是否仍然存在；2）通过光镜放射自显影术确定阿利吉仑的肾脏定位。过表达人肾素和血管紧张素原基因的高血压双转基因大鼠（dTGR）接受阿利吉仑（3mg·kg(-1)·天(-1) sc；渗透型迷你泵）或依那普利（18mg/L 饮用水）治疗。经过 2 周的治疗，dTGR 被分配到继续接受阿利吉仑治疗（“继续”）或停止各自治疗（“停止”）3 周的洗脱期。阿利吉仑和依那普利治疗 1 周可降低血压和白蛋白尿与基线相比。停止任何一种治疗后，血压恢复到治疗前水平，白蛋白尿在 1 周内仍相对较低，但此后两组均以相似的速度升高。相比之下，阿利吉仑（继续和停止治疗组）降低了转化生长因子-β和肾脏胶原 IV 的肾脏 mRNA，但依那普利则没有。胶原 IV 蛋白表达也出现了类似的模式。即使在停止阿利吉仑治疗 3 周后，肾脏中的药物水平仍超过其 IC50，而无法检测到依那普利拉。为了定位阿利吉仑的积累，用[（3）H]-阿利吉仑对 Wistar 大鼠进行了 7 天的治疗。放射自显影显示在肾小球、小动脉和入球小动脉以及远曲小管中存在特异性标记。即使在 7 天的洗脱后，仍能观察到标记。这些结果表明，阿利吉仑的亲肾特性与依那普利不同，这可能有助于这种肾素抑制剂的肾脏保护机制。
