Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan of hypertensive rats

In this study, we investigated the outcome of lifelong treatment with the a ngiotensin II type 1 receptor (AT(1)) blocker fonsartan (HR 720) in young s troke-prone spontaneously hypertensive rats (SHR-SF). In addition to the pr imary end point, lifespan, and to determine the mechanisms involved in the treatment-induced effects, parameters such as left ventricular hypertrophy, cardiac function/metabolism, endothelial function, and the expression/acti vity of endothelial nitric oxide synthase and of angiotensin-converting enz yme (ACE) were also investigated. Ninety 1-month-old SHR-SP were allotted t o 2 groups and treated via drinking water with an antihypertensive dose of forstartan (10 mg.kg(-1) d(-1)) or placebo. Fonsartan doubled the lifespan to 30 months in SHR-SP, which was comparable to the lifespan of normotensiv e Wistar-Kyoto rats. After 15 months, a time when approximate to 80% of the placebo group had died, left ventricular hypertrophy was completely preven ted in fonsartan-treated animals. Furthermore, cardiac function and metabol ism as well as endothelial function were significantly improved. These effe ctsd were correlated with increased endothelial nitric oxide synthase expre ssion in the heart and carotid artery and with markedly decreased tissue AC E expression/activities. Lifespan extension and cardiovascular protection b y long-term AT(1), blockade with fonsartan led to similar beneficial effect s, as observed with long-term ACE inhibition.