Authors
Linz W. Jessen T. Becker RH. Scholkens BA. Wiemer G.
Institution
Hoechst Marion Roussel, DG Research Cardiovascular, Frankfurt/Main, Germany.
wolfgang.Linz@hmrag.com
Title
Long-term ACE
inhibition doubles
lifespan of hypertensive rats.
Source
Circulation. 96(9):3164-72, 1997 Nov 4.
Abstract
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 x
kg(-1) x d(-1)), a nonantihypertensive low dose of ramipril (LRA, 10 microg x
kg(-1) x 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 approximately 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.