LONG-TERM ACE-INHIBITION DOUBLES LIFE-SPAN OF HYPERTENSIVE RATS

Background We compared the outcome of lifelong treatment with the ACE inhibitor ramipril in young prehypertensive stroke-prone spontaneously hypertensive rats (SHR-SP) and age-matched normotensive Wistar-Kyoto (WKY) rats. Ramipril was given in an antihypertensive and subantihyper tensive dose. In addition to the primary end point, lifespan, surrogat e parameters such as cardiac left ventricular hypertrophy, cardiac fun ction and metabolism, and endothelial function were studied. Methods a nd Results One-month-old SHR-SP and WKY rats, 135 of each, were random ized into 3 groups. Each group was treated via drinking water with an antihypertensive high dose of ramipril (HRA, 1 mg.k(-1).d(-1)), a nona ntihypertensive low dose of ramipril (LRA, 10 mu g.kg(-1).d(-1)), or p lacebo. Body weight and blood pressure were determined every 3 months, Molecular, biochemical, and functional data were assessed in SHR-SP a nd WKY rats after 15 and 30 months, respectively. These were the times when approximate to 80% of the corresponding placebo group had died. Early-onset long-term ACE inhibition with HRA doubled lifespan to 30 m onths in SHR-SP, which was identical to the lifespan of placebo-treate d normotensive WKY rats. LRA treatment prolonged lifespan from 15 to 1 8 months. In SHR-SP, left ventricular hypertrophy was completely preve nted by HRA bur not by LRA treatment. Cardiac function and metabolism as well as endothelial function were significantly improved by both do ses of ramipril. Carotid expression of endothelial NO synthase was mod erately enhanced, whereas cardiac ACE expression and activity were dec reased to values of placebo-treated WKY rats. Conclusions Lifelong ACE inhibition doubles lifespan in SHR-SP, matching that of normotensive WKY rats. This effect correlated with preservation of endothelial func tion, cardiac function/size, and metabolism. Thus, these data predict a beneficial outcome on survival in high-risk patients with hypertensi on and associated cardiovascular diseases by ACE inhibition.