Nishijo N, Sugiyama F, Kimoto K, Taniguchi K, Murakami K, Suzuki S, Fukamizu A, Yagami K
Laboratory Animal Research Center, University of Tsukuba, Ibaraki, Japan.
Lab Invest. 1998 Sep;78(9):1059-66.
We studied the effect of excessive salt intake on vascular lesion development in hypertensive transgenic mice that overproduce angiotensin II, ie, Tsukuba hypertensive mice (THM). At 6 weeks of age, THM and C57BL/6J (controls) were given either 1% sodium chloride ("salt-loaded") drinking water or tap water for 30 days. Salt-loaded THM, but not controls, suffered frequent thoracic or abdominal cavity hemorrhage. THM mortality after 7 days of salt loading was 23%; after 30 days of salt loading, it rose to 67%. Hemorrhaging occurred due to the development of aortic aneurysm and rupture at the aortic arch and aorta near the renal arteries. Vascular lesions progressed with structural degeneration of the aortic media. Electronmicroscopic analysis revealed that intact THM already exhibited vascular remodeling consisting of vascular smooth muscle cells (VSMCs) with developed organelles and an increased extracellular matrix. Salt-loaded THM suffered aggravated vascular hypertrophy and vascular structure destruction by plasma material invasion, necrosis of VSMCs possessing extremely swollen cytoplasm and abundant organelles, and interlamellar bleeding, resulting in aortic aneurysm and eventual rupture. Interestingly, blood pressure levels and heart rates in salt-loaded THM did not differ significantly from those of controls; plasma renin activity between drinking regimens was also comparable between the two groups. Drinking volume and the concentration of atrial natriuretic peptide (ANP) in plasma, however, were significantly higher in salt-loaded THM than in intact THM. In addition to aneurysm localization, the findings regarding drinking volume and plasma ANP suggest that aortic aneurysm and rupture in salt-loaded THM occurred as the result of an unknown mechanical stress, other than blood pressure, on the aortic wall. High salt ingestion is involved in the development of thoracic and abdominal aortic aneurysm in the presence of hypertension in the activated renin-angiotensin system. THM should therefore serve as a useful animal model for studying the pathogenesis of aortic aneurysm accompanied by hypertension.
我们研究了过量盐摄入对过度产生血管紧张素II的高血压转基因小鼠（即筑波高血压小鼠，THM）血管病变发展的影响。6周龄时，给THM和C57BL/6J（对照）饮用1%氯化钠（“高盐”）饮用水或自来水，持续30天。高盐组的THM出现频繁的胸腔或腹腔出血，而对照组未出现。高盐摄入7天后THM的死亡率为23%；高盐摄入30天后，死亡率升至67%。出血是由于主动脉瘤形成以及主动脉弓和肾动脉附近主动脉的破裂所致。血管病变随着主动脉中膜的结构退化而进展。电子显微镜分析显示，正常的THM已经表现出血管重塑，其特征为血管平滑肌细胞（VSMC）细胞器发达且细胞外基质增加。高盐组的THM出现血管肥大加重和血管结构破坏，原因包括血浆物质侵入、细胞质极度肿胀且细胞器丰富的VSMC坏死以及层间出血，最终导致主动脉瘤并破裂。有趣的是，高盐组THM的血压水平和心率与对照组相比无显著差异；两组不同饮水方案下的血浆肾素活性也相当。然而，高盐组THM的饮水量和血浆心房利钠肽（ANP）浓度显著高于正常THM。除了动脉瘤的定位，关于饮水量和血浆ANP的研究结果表明，高盐组THM的主动脉瘤和破裂是由主动脉壁上除血压之外的未知机械应力导致的。在激活的肾素 - 血管紧张素系统存在高血压的情况下，高盐摄入参与了胸主动脉瘤和腹主动脉瘤的发展。因此，THM应作为研究伴有高血压的主动脉瘤发病机制的有用动物模型。
