Papademetriou Vasilios, Mammillot Philippe, Redman Robert, Notargiacomo Aldo, Narayan Puneet, Lakshman Raj
The Va Medical Center and Georgetown University and the George Washington University Washington D.C. USA, papavip@ aol.com.
The Va Medical Center and Georgetown University and the George Washington University Washington D.C. USA.
J Renin Angiotensin Aldosterone Syst. 2001 Mar;2(1_suppl):S77-S80. doi: 10.1177/14703203010020011301.
Several studies indicate that blockade of the renin-angiotensin-aldosterone system (RAAS) can prevent atherosclerosis and vascular events, but the precise mechanisms involved are still unclear. In this study, we investigated the effect of the AT 1-receptor blocker, candesartan, in the prevention of atherosclerosis in Watanabe heritable hyperlipidaemic (WHHL) rabbits and also the effect of AT1-receptor blockade in the uptake of oxidised LDL by macrophage cell cultures. In the first set of experiments, 12 WHHL rabbits were randomly assigned to three groups: placebo, atenolol 5 mg/kg daily or candesartan 2 mg/kg daily for six months. Compared with controls and atenolol-treated rabbits, candesartan treatment resulted in a significant 50-60% reduction of atherosclerotic plaque formation and a 66% reduction in cholesterol accumulation in the thoracic aorta. Studies in macrophage cultures indicated that candesartan prevented uptake of oxidised LDL-(oxLDL)-cholesterol by cultured macrophages. Candesartan inhibited the uptake of oxLDL in a dose-dependent manner, reaching a maximum inhibition of 70% at concentrations of 5.6 µg/ml. Further studies in other animal models and well-designed trials in humans are warranted to further explore the role of AT1-receptor blockade in the prevention of atherosclerosis.
多项研究表明，阻断肾素-血管紧张素-醛固酮系统（RAAS）可预防动脉粥样硬化和血管事件，但其确切机制仍不清楚。在本研究中，我们调查了AT1受体阻滞剂坎地沙坦对渡边遗传性高脂血症（WHHL）兔动脉粥样硬化的预防作用，以及AT1受体阻断对巨噬细胞培养物摄取氧化型低密度脂蛋白（oxLDL）的影响。在第一组实验中，12只WHHL兔被随机分为三组：安慰剂组、每日给予阿替洛尔5mg/kg组或每日给予坎地沙坦2mg/kg组，为期6个月。与对照组和阿替洛尔治疗的兔子相比，坎地沙坦治疗使动脉粥样硬化斑块形成显著减少50%-60%，胸主动脉胆固醇蓄积减少66%。巨噬细胞培养研究表明，坎地沙坦可阻止培养的巨噬细胞摄取氧化型低密度脂蛋白胆固醇（oxLDL-胆固醇）。坎地沙坦以剂量依赖方式抑制oxLDL的摄取，在浓度为5.6μg/ml时达到最大抑制率70%。有必要在其他动物模型中进行进一步研究，并在人体中开展精心设计的试验，以进一步探索AT1受体阻断在预防动脉粥样硬化中的作用。
