(Circulation. 1997;96:3164-3172.)
© 1997 American Heart Association, Inc.
Articles |
Long-term ACE Inhibition Doubles Lifespan of Hypertensive Rats
From Hoechst Marion Roussel, DG Research Cardiovascular, Frankfurt/Main, Germany.
Correspondence to Dr Wolfgang Linz, Hoechst-Marion-Roussel, DG Research Cardiovascular (H821), D-65926 Frankfurt/Main, Germany. E-mail wolfgang.Linz{at}hmrag.com
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 subantihypertensive dose. In addition to the primary end point, lifespan, surrogate parameters such as cardiac left ventricular hypertrophy, cardiac function and metabolism, and endothelial function were studied.
Methods and Results One-month-old SHR-SP and WKY rats, 135
of each, were randomized into 3 groups. Each group was treated via
drinking water with an antihypertensive high dose of ramipril (HRA, 1
mg · kg-1 ·
d-1), a nonantihypertensive low dose of
ramipril (LRA, 10 µg · kg-1 ·
d-1), or placebo. Body weight and blood
pressure were determined every 3 months. Molecular, biochemical, and
functional data were assessed in SHR-SP and WKY rats after 15 and 30
months, respectively. These were the times when 
80% of the
corresponding placebo group had died. Early-onset long-term ACE
inhibition with HRA doubled lifespan to 30 months in SHR-SP, which was
identical to the lifespan of placebo-treated normotensive WKY rats. LRA
treatment prolonged lifespan from 15 to 18 months. In SHR-SP, left
ventricular hypertrophy was completely
prevented by HRA but not by LRA treatment. Cardiac function and
metabolism as well as endothelial function
were significantly improved by both doses of ramipril. Carotid
expression of endothelial NO synthase was moderately
enhanced, whereas cardiac ACE expression and activity were decreased 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 function, cardiac function/size, and metabolism. Thus, these data predict a beneficial outcome on survival in high-risk patients with hypertension and associated cardiovascular diseases by ACE inhibition.
Key Words: ramipril • survival • endothelium
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