Effect of nitric oxide, antioxidants and pravastatin on experimental atherosclerosis in male New Zealand white [NZW] rabbits

ABSTRACT

Atherosclerosis is considered one of the major causes of human morbidity and mortality all over the world. In this work, an attempt was done to investigate the possible role of nitric oxide [NO] on modulation of experimentally-induced atherosclerosis in male New Zealand White [NZW] rabbits. For this purpose, 64 male NZW rabbits were left for 2 weeks to acclimatize to laboratory conditions before being included in this experiment. Rabbits were then randomly classified into 8 equal groups. The first group [control, C] was fed commercial chow and the second group [atherosclerotic, A] was fed an atherogenic diet [containing 1% cholesterol]. The last 6 groups [VCA, AA, NSA, NA, PA and PNA groups] were fed the atherogenic diet in addition to the following respectively [vitamin C, L-arginine, Nigella sativa [NS], N-Nitro- L-arginine methyl ester [L-NAME], pravastatin and L-NAME with pravastatin]. The different feeding regimen and treatments were continued for 2 months. After 2 months, rabbits were killed to evaluate the severity of atherosclerosis and the effect of the different treatments given. The following parameters were assayed [plasma lipid profile, malondialdehydes [MDA], total antioxidant status [TAS] and nitrites; aortic tissue prostaglandin E[2][PGE[2]] and histological examination]. The atherogenic diet induced a significant increase in plasma total cholesterol [TC], triglycerides [TG], low density lipoprotein [LDL], high density lipoprotein [HDL] and MDA compared to C group. The TAS, nitrites and aortic PGE[2] were significantly decreased compared to control values. These atherogenic changes were reflected on the histopathological changes observed in aortic tissues from the A group. Vitamin C [500 mg/kg/day, orally] improved the atherogenic changes when given to atherosclerotic rabbits. There was a significant increase in TAS, nitrites and aortic PGE[2] associated with a significant decrease in MDA associated with improvement in the histopathological picture of aortic tissue of VCA group compared to A group. Administration of NS to atherosclerotic rabbits produced significant decrease in TC, TG, LDL and MDA and significant increase in HDL, TAS, nitrites and PGE[2] in NSA group compared with A group. These effects were associated with improvement in the histopathological picture of aortic tissue of NSA group compared with A group. L-arginine produced significant decrease in MDA and significant increase in TAS nitrites and PGE[2] in AA group compared with A group. In NA group, L-NAME aggravated atherosclerosis as evidenced by a significant increase in MDA, significant decrease in TAS, nitrites and PGE[2] and aggravation of the atherogenic changes in aortic tissue compared with A group. Pravastatin improved all atherogenic changes in PA group compared with A group. There were significant decrease in TC, TG, LDL and MDA with significant increase in HDL, TAS, nitrites and aortic PGE[2]. This protective effect of pravastatin was reflected on the histopathological picture of aortic tissue. In PNA group, L-NAME antagonized the protective effect of pravastatin. It was concluded that atherosclerosis is a multifactorial disease. The increase in free radicals [FR] and lipid peroxidation and the decrease in NO and PGE[2] are the main contributors of atherosclerosis. The antiatherogenic effects of pravastatin depend upon its plasma lipid lowering and antioxidant effects, in addition to increase intimal NO and PGE[2] production. L-NAME antagonized the antiatherogenic effects of pravastatin. The antiatherogenic effects of Nigel/a saliva and vitamin C depend mainly on their antioxidant action. Other mechanisms may contribute such as decrease in lipid profile [Nigella saliva] and increase in NO and PGE[2] production [Nigella saliva and Vitamin C]. These findings suggest that pravastatin is the most effective antiatherosclerotic agent followed by Nigella saliva and high dose of vitamin C. So, it is recommended that addition of Nigella saliva and/or antioxidant vitamins [such as vitamins C] to potentiate the antiatherogenic effects of pravastatin in atherosclerotic patients. This will also reduce the cost of treatment and side effects of drugs