Cristofori, Patrizia; (2006) Experimental studies on the anti-atherosclerotic properties of lacidipine. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Atherosclerosis is the major form of heart disease in Western countries. Atherosclerosis is a slowly progressing complex disease in which deposits build up in the inner lining of arteries causing the formation of plaques. Plaque formation is a multi-stage process which results in decreased arterial blood flow. The long-lasting calcium antagonist lacidipine is believed to affect many of the steps related to plaque formation and plaque development. Various animal models have been used to date to study experimental atherosclerosis and reproduce lesions comparable to those occurring in man. In the present studies the hamster and the apoE-decient mouse were the animal models of choice to investigate the basis of the anti-atherosclerotic properties of lacidipine. Experiments demonstrated that in the hamster and the apoE-deficient mouse fed a standard rodent diet, lacidipine treatment reduced the extent of atherosclerotic activity, without lowering hypercholesterolemia. The drug also significantly reduced endothelial cell changes associated with atherosclerosis. Moreover, in the apoE-deficient mouse fed a high-fat diet, lacidipine decreased plasma low density lipoprotein (LDL) oxidation and confirmed that the susceptibility of LDL to oxidation is related to increased atherosclerotic risk. In addition, it was demonstrated that lacidipine can maintain endothelial nitric oxide levels at nano molar concentrations, which protects against vascular injury. Finally, lacidipine was shown to have a significant inhibitory effect on cholesterol esterification and matrix metalloproteinases activity, properties which may also contribute to increased plaque stability. In conclusion, it is proposed that lacidipine influences the atherogenic process by specific mechanisms, which are the result of a combined potent and long-lasting calcium antagonism, in conjunction with powerful antioxidant properties. These activities are further enhanced by the high lipophilicity of the drug.

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