Valsartan augments the beneficial effect of rosuvastatin with respect to lipid profile, oxidative stress, and the nitric oxide pathway in high-fat diet-induced hypercholesterolemic rats

Abstract

BackgroundThe renin-angiotensin system contributes considerably to a variety of cardiovascular diseases and is the target of angiotensin receptor blockers (ARBs). Recent studies have reported that in experimental models, as well as some human studies, ARBs had shown the ability to affect lipid metabolism in a modest but significant way. In addition to their primary mode of action, statins and ARBs have common additional properties such as restoration of endothelial activity and antioxidant properties. These properties may potentially aid the improvement treatment of cardiovascular disease.ObjectiveThe present study was designed to evaluate the possible beneficial effects of both therapies valsartan (ARB) and rosuvastatin (3-hydroxy-methylglutaryl coenzyme reductase inhibitor) beyond their blood pressure-lowering and cholesterol-lowering effects, and the possibility that valsartan may enhance the beneficial effects of rosuvastatin in high-fat diet-induced hypercholesterolemic (HC) rats with respect to lipid profile, oxidative stress, and the nitric oxide pathway.Materials and methodsHC was induced in male albino Wistar rats by a daily gavage of a cocktail containing 1 l peanut oil, 100 g cholesterol, and 100 g cholic acid over a period of 21 days. These animals were assigned randomly to the following groups: HC, HC/rosuvastatin, HC/valsartan, and HC/rosuvastatin+valsartan.ResultsDaily gavage of the cocktail for 3 weeks induced a significant increase in plasma total cholesterol (TC), triglyceride (TG), and low-density lipoprotein and a significant reduction in high-density lipoprotein (HDL), but did not induce any significant changes in arterial blood pressure and heart rate. Meanwhile, the plasma nitric oxide level was reduced to 17.49% of its normal level and the plasma malondialdehyde level was significantly increased by 32.53%. Coadministration of valsartan with rosuvastatin normalized plasma HDL, significantly decreased plasma TC and low-density lipoprotein to a greater extent than monotherapy with each drug as well as ameliorated the effect of HC diet on the plasma TG level in HC rats. Moreover, the combined treatment induced a significant increase in the plasma nitrate+nitrite level compared with the corresponding HC value and normalized the plasma malondialdehyde level with respect to the effect of rosuvastatin or valsartan alone. In addition, histopathological and morphometric studies of the aorta and liver showed marked improvement after combined treatment with rosuvastatin and valsartan when compared with the HC group.ConclusionConclusively, coadministration of rosuvastatin and valsartan in high-fat diet-induced HC rats conferred a greater degree of protection as it ameliorated the increase in the plasma TC and TG and restored HDL to its normal value, improved the endothelial function, and reduced oxidative stress, together with improvement in the histopathological features in rats that had previously received a high-fat diet.