Improvement of endothelial function in insulin-resistant carotid arteries treated with pravastatin

Abstract

Object. Insulin resistance and hypertension are independent risk factors for stroke. Endothelial dysfunction in response to risk factors and carotid artery (CA) disease are important in the pathogenesis of stroke. Pravastatin may have cholesterol-independent pleiotropic effects. In the present study the authors examined the effects of short-course pravastatin treatment on endothelial function in CAs obtained in control and insulin-resistant rats with fructose-induced hypertension. Methods. Thirty rats were divided into two experimental groups, in which 14 were fed a regular diet and 16 were fed a fructose-enriched diet for 3 weeks. The rats were then divided into four groups: control, pravastatin-treated control, fructose-fed, and pravastatin-treated fructose-fed. Pravastatin was administered (20 mg/kg/day) for 2 weeks. Excretion of the urinary nitric oxide (NO) metabolite nitrite (NO₂⁻) was also assayed. The CAs from all rats were subsequently removed and assessed for endothelium-dependent and -independent vascular reactivity in vitro. The rats in the fructose-fed group were insulin resistant, hyperinsulinemic, and hypertensive relative to the rats in the control and pravastatin-treated control groups and exhibited diminished endothelium-dependent vasomotion and urinary NO₂⁻ excretion (p < 0.05), with preserved endothelium-independent vasomotion. Strikingly, pravastatin treatment restored endothelium-dependent vasomotion and urinary NO₂⁻ excretion in rats in the fructose-fed pravastatin-treated relative to the fructose-fed group (p < 0.05). Conclusions. The authors report, for the first time, that pravastatin restores endothelial function in CAs from insulin-resistant rats with fructose-induced hypertension. These beneficial effects were ascribed to direct, cholesterol-independent vascular effects of pravastatin and are likely the result of augmentation of NO production. These data provide impetus for further investigation of nonlipid-lowering indications for pravastatin therapy in the prevention and treatment of CA disease.