Effects of atorvastatin,amlodipine,and their combination on vascular dysfunction in insulin-resistant rats

Deficiency of tetrahydrobiopterin (bh4) in the vascular tissue contributes to endo-thelial dysfunction through reduced enos activity and increased superoxide anion (o2 -) generation in the insulin-resistant state. we investigated the effects of atorvastatin,a 3-hydroxyl-3-methylglutaryl coenzyme a (hmg coa) reductase inhibitor; amlodipine,a calcium antagonist; and their combination on blood pressure,arterial relaxation and contraction,and vascular oxidative stress in aortas of high fructose-fed rats. oral administration of atorvastatin for 8 weeks did not significantly lower blood pressure,but normalized angiotensin ii-induced vasoconstriction and endothelial function in the fructose-fed rats. atorvastatin treatment of fructose-fed rats increased vascular bh4 content,which was associated with an increase in endothelial no synthase activity as well as a reduction in endothelial o2 - production. on the other hand,administration of amlodipine did not affect the angiotensin ii-induced vasoconstriction and endothelial function,but normalized the elevated blood pressure in the fructose-fed rats. the combined treatment did not show synergistic but additive beneficial effects. the present study suggests that combined therapy of hmg-coa reductase inhibitors and calcium antagonists prevents functional vascular disorders in the insulin-resistant state,possibly resulting in the protection against or delay of development of hypertension,vascular dysfunction in diabetes,and thereafter atherosclerosis. © the japanese pharmacological society.