CARDIAC MYOCYTE NECROSIS INDUCED BY ANGIOTENSIN-II
CARDIAC MYOCYTE NECROSIS INDUCED BY ANGIOTENSIN-II
复制标题
DOI：
10.1161/01.res.69.5.1185
复制
发表时间：
1991-11-01
影响因子：
20.1
通讯作者：
WEBER, KT
中科院分区：
文献类型：
--
作者：
TAN, LB;JALIL, JE;WEBER, KT
虽然血管紧张素II（Ang II）在心力衰竭的发病机制和进展中的作用尚不确定，但以前的报道表明，心肌细胞损伤可能是这一过程的一个组成部分。在这项研究中，我们更详细地研究了这种可能性。在90只大鼠中检查了非急性高血压剂量的Ang II的毒性作用，包括接受血管紧张素输注（200 ng/min i. p.）肾血管性高血压患者，内源性血管紧张素II的刺激发生。通过1）肌球蛋白的体内单克隆抗体标记后的免疫荧光检测异常肌膜通透性，2）[H-3]胸苷掺入DNA检测成纤维细胞增殖，和3）肌细胞溶解和随后瘢痕形成的光学显微镜证据，评价这些处理导致的肌细胞损伤和伤口愈合。我们发现，外源性血管紧张素II产生多灶性抗肌球蛋白标记的心肌细胞和肌细胞溶解，这是最大的第1-2天的输液。随后，DNA合成速率增加，成纤维细胞增殖在第2天达到峰值水平（Ang II治疗大鼠，90.0 +/- 18.6 cpm/μ g DNA;对照大鼠，11.4 +/- 2.3 cpm/μ g DNA; p < 0.05）;在第14天发现显微镜下瘢痕形成，占心肌的0.12 +/- 0.02%。同时给予普萘洛尔（30 mg/kg/天s.c.）和酚苄明（5 mg/kg/天i.m.）没有减弱Ang II诱导的抗肌球蛋白标记。增加内源性血管紧张素II，导致肾缺血后腹主动脉缩窄，产生抗肌球蛋白标记和增加的DNA合成率一样，与血管紧张素II输注观察。肌细胞损伤和纤维组织增生均用卡托普利（65 mg/天p.o.）预防，而利血平预处理则无此保护作用。另一方面，无肾缺血的肾主动脉结扎可产生高血压，但无坏死。我们的结论是，病理生理水平的内源性以及低剂量的外源性血管紧张素II与改变肌膜通透性和肌细胞溶解与随后的成纤维细胞增殖和瘢痕形成。心肌细胞损伤与高血压或增强的血管紧张素II的肾上腺素能效应或高血压本身无关。卡托普利可有效预防肾血管性高血压时心肌细胞损伤。负责血管紧张素II诱导的坏死的机制将需要进一步研究。
Although the role of angiotensin II (Ang II) in the pathogenesis and progression of the failing heart is uncertain, previous reports have suggested that myocyte injury may be a component in this process. In this study, we investigated this possibility in more detail. Cardiotoxic effects of nonacutely hypertensive doses of Ang II were examined in 90 rats, including those receiving an angiotensin infusion (200 ng/min i.p.) and those with renovascular hypertension, where endogenous stimulation of Ang II occurred. Myocyte injury and wound healing resulting from these treatments were evaluated by 1) immunofluorescence after in vivo monoclonal antibody labeling of myosin to detect abnormal sarcolemmal permeability, 2) [H-3]thymidine incorporation into DNA, to detect fibroblast proliferation, and 3) light microscopic evidence of myocytolysis and subsequent scar formation. We found that exogenous Ang II produced multifocal antimyosin labeling of cardiac myocytes and myocytolysis, which were maximal on days 1-2 of the infusion. Subsequently, DNA synthesis rates were increased, with fibroblast proliferation reaching peak levels on day 2 (Ang II-treated rats, 90.0 +/- 18.6 cpm/mu-g DNA; control rats, 11.4 +/- 2.3 cpm/mu-g DNA; p < 0.05); microscopic scarring was found on day 14 and represented 0.12 +/- 0.02% of the myocardium. Concurrent treatment with both propranolol (30 mg/kg/day s.c.) and phenoxybenzamine (5 mg/kg/day i.m.) did not attenuate Ang II-induced antimyosin labeling. Increased endogenous Ang II, resulting from renal ischemia after abdominal aortic constriction, produced both antimyosin labeling and increased rates of DNA synthesis like that observed with Ang II infusion. Both myocyte injury and fibroplasia were prevented with captopril (65 mg/day p.o.), but this protective effect was not seen with reserpine pretreatment. Infrarenal aortic banding without renal ischemia, on the other hand, produced hypertension without necrosis. We conclude that pathophysiological levels of endogenous as well as low-dose exogenous Ang II were associated with altered sarcolemmal permeability and myocytolysis with subsequent fibroblast proliferation and scar formation. Myocyte injury was unrelated to the hypertensive or enhanced adrenergic effects of Ang II or to hypertension per se. Captopril was effective in preventing myocyte injury in renovascular hypertension. The mechanism(s) responsible for Ang II-induced necrosis will require further study.