Synergistic effect of angiotensin-converting enzyme (ACE) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibition on inflammatory markers in atherosclerotic rabbits

Abstract

In the present study, we compared the effect of atorvastatin (1 mg.kg(-1).day(-1)) and quinapril (0.5 mg.kg(-1).day(-1)) alone or in combination on inflammatory markers, endothelial function, intimal thickening and fibrinolytic balance in rabbits fed with either a control diet or a diet containing 1% (v/v) cholesterol for 12 weeks. Atorvastatin alone or in combination partially prevented the increase in cholesterol plasma levels observed in rabbits fed with the cholesterol-rich diet, but did not modify blood pressure levels. Quinapril administration did not alter any of these parameters in any group. Hypercholesterolaemia increased plasma levels of interleukin-1beta, interleukin-6, interferon-gamma and C-reactive protein, reduced acetylcholine-induced relaxation and produced intimal thickening. Likewise, atherosclerotic rabbits had reduced plasma tissue-type plasminogen activator activity and D-dimer levels and an increase in plasminogen-activator inhibitor-1 activity. Both drugs enhanced acetylcholine-induced relaxation, reduced intimal thickening and improved fibrinolytic balance in atherosclerotic rabbits in a similar manner. Their combination did not induce additive effects on these parameters. However, only the combination of both drugs was able to prevent the increase in inflammatory markers induced by hypercholesterolaemia. In summary, these data suggest that quinapril and atorvastatin had comparable beneficial effects on the alterations of vascular function and structure as well as fibrinolytic balance in atherosclerotic rabbits. In addition, the combination of atorvastatin and quinapril exerts a synergistic effect on inflammatory markers, which individual treatment, at the doses used, was not able to modify.

Antiatherosclerotic potential of aliskiren: its antioxidant and anti-inflammatory effects in rabbits: a randomized controlled trial

“…Plasma levels of platelet activating factor (PAF) are elevated in hypercholesterolemia [29], PAF is known to stimulate granulocytes to release cytokines such as TNF-α [30] which stimulates nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) in the endothelial cells to generate ROS [31] and INF-γ [32] which activate granulocytes to generate ROS [33]. In addition hypercholesterolemia increases synthesis of arachidonic acid and prostaglandins [34].…”

Statins: another class of antihypertensive agents?

“…[122][123][124] The addition of a statin has also been shown to have an additional effect on reducing left ventricular mass (a powerful predictor of cardiovascular events) in patients with systemic hypertension and hyperlipidaemia on antihypertensive agents and diet. 125 In this context, the Hypertension High Risk Management (HYRIM) 126 trial investigated the effects of fluvastatin and lifestyle intervention in drug-treated hypertensive patients with the primary end point being carotid intima-media thickness (IMT) progression over 4 years.…”

Anti-inflammatory Actions of Quinapril

“…Quinapril in combination with atorvastatin did not affect levels of these cytokines in normal rabbits. [55] These effects were accomplished without accompanying changes in either arterial blood pressure or plasma cholesterol and imply that lower doses of these drugs in combination could have beneficial effect on inflammation without impacting blood pressure or cholesterol levels. In this model, other markers of inflammation, such as MCP-1, IL-8, and platelet derived growth factor (PDGF-B), were also reduced by quinapril treatment.…”

“…Atherosclerotic aortic rings from rabbits fed a high-cholesterol diet showed a reduced lumen and a reduced vasorelaxation response to acetylcholine; quinapril partially prevented these changes. [55] Quinapril and atorvastatin together, but not alone, prevented hypercholesterolemiainduced increases in inflammatory markers IL-6, IL-1β, interferon gamma, and C-reactive protein (CRP). Quinapril in combination with atorvastatin did not affect levels of these cytokines in normal rabbits.…”