Raicu M, Pojoga L, Simionescu N, Simionescu M
Institute of Cellular Biology and Pathology, Nicolae Simionescu, Bucharest, Rumania.
J Submicrosc Cytol Pathol. 1996 Apr;28(2):265-75.
We compared the effect of two different calcium channel blockers (CCB), Nifedipine (1,4-dihydropyridine calcium antagonist) and Diltiazem (a benzothiazepine agent) on plasma components and the development of atherosclerotic plaque in experimental hypercholesterolemia. Golden male Syrian hamsters were divided into four groups: atherogenic animals (AT) induced by standard diet supplemented with 3% cholesterol and 15% butter; AT animals treated with Nifedipine (20 or 60 mg/kg/day); AT hamsters treated with Diltiazem (45 mg/kg/day) and controls (C), fed a standard chow diet. For one month, the drugs were administered concomitantly with the atherogenic diet. During the experiment, serum cholesterol, free calcium and angiotensin-converting enzyme (ACE) activity values were determined. Specimens from the lesion-prone areas: aortic valves, coronary arteries, and aortic arch, were collected and processed for light and electron microscopy. The results show that the atherogenic diet induces a significant increase of serum cholesterol (389 +/- 67.47 mg/dl), free calcium (13.44 +/- 0.84 mg/dl) and ACE activity (78.46 +/- 9.25 mU/ml) as compared to controls (cholesterol 73.76 +/- 3.31 mg/dl; calcium 8.9 +/- 0.5 mg/dl; ACE 33.68 +/- 2.6 mU/ml). Administration of Diltiazem reduced significantly these parameters (cholesterol, 196.25 +/- 22 mg/dl; calcium, 8.41 +/- 0.6 mg/dl) while Nifedipine had no effect (cholesterol, 283.03 +/- 44.7 mg/dl; calcium, 11.13 +/- 1.25 mg/dl) and increased the ACE activity (100.28 +/- 36.9 mU/ml). At the structural level, a significant correlation between the apparition and progression of the atherosclerotic lesions and the biochemical parameters detected, was observed. Diltiazem treated animals showed a reduction in the lesion severity, at the level of aortic valves, coronary arteries and aortic arch; we assume that Diltiazem acts on the early phases of atherosclerosis by blocking the lipid transport and accumulation into the subendothelial space. In contradistinction, Nifedipine treatment failed to suppress the atherogenic effect of fat-rich diet, and as in AT hamsters, the plaques developed in all lesion-prone areas. The latter were characterised by numerous lipid-laden cells (in aorta and aortic valves) and calcification and necrotic centres, in all locations, including coronary arteries. The results suggest a different mechanism of action and the ensuing effects of various CCB on atherogenesis.
我们比较了两种不同的钙通道阻滞剂（CCB），硝苯地平（一种1,4 - 二氢吡啶类钙拮抗剂）和地尔硫䓬（一种苯并硫氮䓬类药物）对实验性高胆固醇血症血浆成分及动脉粥样硬化斑块形成的影响。雄性叙利亚金黄地鼠被分为四组：由补充3%胆固醇和15%黄油的标准饮食诱导产生动脉粥样硬化的动物组（AT）；用硝苯地平（20或60毫克/千克/天）治疗的AT动物组；用地尔硫䓬（45毫克/千克/天）治疗的AT仓鼠组以及喂食标准普通饮食的对照组（C）。药物与致动脉粥样硬化饮食同时给药一个月。实验期间，测定血清胆固醇、游离钙和血管紧张素转换酶（ACE）活性值。收集病变易发生部位（主动脉瓣、冠状动脉和主动脉弓）的标本，进行光镜和电镜处理。结果显示，与对照组相比（胆固醇73.76±3.31毫克/分升；钙8.9±0.5毫克/分升；ACE 33.68±2.6毫单位/毫升），致动脉粥样硬化饮食使血清胆固醇（389±67.47毫克/分升）、游离钙（13.44±0.84毫克/分升）和ACE活性（78.46±9.25毫单位/毫升）显著升高。地尔硫䓬给药显著降低了这些参数（胆固醇，196.25±22毫克/分升；钙，8.41±0.6毫克/分升），而硝苯地平则无此作用（胆固醇，283.03±44.7毫克/分升；钙，11.13±1.25毫克/分升），且增加了ACE活性（100.28±36.9毫单位/毫升）。在结构层面，观察到动脉粥样硬化病变的出现和进展与所检测的生化参数之间存在显著相关性。地尔硫䓬治疗的动物在主动脉瓣、冠状动脉和主动脉弓水平的病变严重程度有所降低；我们推测地尔硫䓬通过阻断脂质转运和在血管内皮细胞下空间的积聚作用于动脉粥样硬化的早期阶段。相反，硝苯地平治疗未能抑制富含脂肪饮食的致动脉粥样硬化作用，并且与AT仓鼠一样，在所有病变易发生部位都形成了斑块。后者的特征是在所有部位，包括冠状动脉，都有大量充满脂质的细胞（在主动脉和主动脉瓣中）以及钙化和坏死中心。结果表明不同CCB在动脉粥样硬化发生过程中的作用机制及后续效应有所不同。
