Effects of telmisartan or amlodipine monotherapy versus telmisartan/amlodipine combination therapy on vascular dysfunction and oxidative stress in diabetic rats

Abstract

Our previous studies identified potent antioxidant effects and improvement of vascular function by telmisartan therapy in experimental diabetes and nitrate tolerance. The present study compared the beneficial effects of single telmisartan or amlodipine versus telmisartan/amlodipine combination therapy (T+A) in streptozotocin (STZ)-induced type 1 diabetic rats. Male Wistar rats were injected once with STZ (60 mg/kg, i.v.) and 1 week later the drugs (telmisartan, amlodipine, or T+A) were administrated orally by a special diet (2.5-5 mg kg(-1) day(-1)) for another 7 weeks. We only observed a marginal beneficial on-top effect of T+A therapy over the single drug regimen that was most evident in the improvement of endothelial function (acetylcholine response) and less pronounced in the reduction of whole blood, vascular and cardiac oxidative stress (blood leukocyte oxidative burst, aortic dihydroethidine and 3-nitrotyrosine staining, as well as cardiac NADPH oxidase activity and uncoupling of endothelial nitric oxide synthase) in diabetic rats. These effects on oxidative stress parameters were paralleled by those on the expression pattern of NADPH oxidase and nitric oxide synthase isoforms. In addition, development of mild hypotension in the T+A-treated rats was observed. Reasons for this moderate synergistic effect of T+A therapy may be related to the potent beneficial effects of telmisartan alone and the fact that amlodipine and telmisartan share similar pathways to improve endothelial function. Moreover, hypotension in the T+A-treated rats could partially antagonize the beneficial additive effects by counter-regulatory mechanisms (e.g., activation of the renin-angiotensin-aldosterone system).