Zhang Guo-Xing, Ohmori Koji, Nagai Yukiko, Fujisawa Yoshihide, Nishiyama Akira, Abe Youichi, Kimura Shoji
Department of Pharmacology, Kagawa University Medical School, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan.
J Mol Cell Cardiol. 2007 Apr;42(4):804-11. doi: 10.1016/j.yjmcc.2007.01.012. Epub 2007 Feb 3.
Elevated activities of the sympathetic nerve and renin-angiotensin systems are common features of heart failure. This study was designed to investigate the roles of the AT1 receptor in cardiac hypertrophy and oxidative stress during excessive beta-adrenoceptor stimulation using an AT1 receptor antagonist (ARB) and AT1a receptor-deficient (AT1aR(-/-)) mice. Isoproterenol (ISO) was given to C57BL mice with or without ARB (olmesartan) treatment and to AT1aR(-/-) mice by a subcutaneously implanted osmotic mini-pump for 11 days at a rate of 15 mg/kg/day. Chronic ISO infusion to C57BL mice caused concentric cardiac hypertrophy (sham; 4.1+/-0.1, ISO; 5.2+/-0.2 mg/g heart to body weight ratio), accompanied by enhancement of cardiac collagen accumulation, lipid peroxidation, superoxide generation and NADPH oxidase activity. The AT1a and beta-1,2 receptor mRNA expressions were down-regulated in the heart of ISO-infused mice. Olmesartan markedly suppressed cardiac mass enlargement as well as increases of oxidative indicators without any effects on heart rate. Olmesartan did not affect the cardiac angiotensin and beta-adrenergic receptor mRNA expression patterns. The AT1a receptor contribution to ISO-induced cardiac hypertrophy was reproduced in AT1aR(-/-) mice. These data suggest that the AT1 receptor plays a crucial role in the development of cardiac hypertrophy and oxidative stress under excessive beta-adrenergic stimulation, and that ARB treatment is beneficial for sympatho-excitatory cardiac hypertrophy and failure in mice.
交感神经和肾素 - 血管紧张素系统活性升高是心力衰竭的常见特征。本研究旨在使用AT1受体拮抗剂（ARB）和AT1a受体缺陷（AT1aR(-/-)）小鼠，研究AT1受体在过度β - 肾上腺素能受体刺激期间对心肌肥大和氧化应激的作用。通过皮下植入渗透微型泵，以15mg/kg/天的速率，对有或无ARB（奥美沙坦）治疗的C57BL小鼠以及AT1aR(-/-)小鼠给予异丙肾上腺素（ISO），持续11天。对C57BL小鼠进行慢性ISO输注导致向心性心肌肥大（假手术组；4.1±0.1，ISO组；5.2±0.2mg/g心脏与体重比），同时伴有心脏胶原积累、脂质过氧化、超氧化物生成和NADPH氧化酶活性增强。在接受ISO输注的小鼠心脏中，AT1a和β - 1,2受体mRNA表达下调。奥美沙坦显著抑制心脏质量增大以及氧化指标的升高，而对心率无任何影响。奥美沙坦不影响心脏血管紧张素和β - 肾上腺素能受体mRNA表达模式。在AT1aR(-/-)小鼠中再现了AT1a受体对ISO诱导的心肌肥大的作用。这些数据表明，在过度β - 肾上腺素能刺激下，AT1受体在心肌肥大和氧化应激的发展中起关键作用，并且ARB治疗对小鼠交感神经兴奋性心肌肥大和心力衰竭有益。
