(Hypertension. 1999;34:291-295.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Late Treatment With Ramipril Increases Survival in Old Spontaneously Hypertensive Rats
From Hoechst Marion Roussel, DG Cardiovascular Diseases, (W.L., P.W., B.A.S., R.H.A.B., G.W.), Frankfurt/Main, Germany and the Department of Chemistry, Center for Biomedical Research, (T.M.), Oakland University, Rochester, Mich.
Correspondence to Wolfgang Linz, PhD, Hoechst Marion Roussel, DG Cardiovascular Research (H813), D-65926 Frankfurt/Main, Germany. E-mail wolfgang.linz{at}hmrag.com
Abstract—Spontaneously
hypertensive rats (SHR) begin to die from
cardiovascular complications at 
15 months of age. We
tested whether chronic ACE-inhibitor treatment would extend
the lifespan of such old animals. We also studied cardiac
hypertrophy and function, endothelial
function and expression, and activity of NO synthase (eNOS). One
hundred 15-month-old SHR were randomized into 3 groups, control (n=10),
placebo-treated (n=45), and ramipril-treated with an antihypertensive
dose of 1 mg · kg-1 · d-1 in
drinking water (n=45). Ex vivo experiments were performed after 15
months (control) and 21 months, when 80% of the placebo group had
died. Late treatment with ramipril significantly extended lifespan of
the animals from 21 to 30 months. Fully established cardiac
hypertrophy, observed in placebo-treated animals and in
controls, was significantly reversed by ramipril treatment. In isolated
working hearts, a significantly improved function associated with
increased cardiac eNOS expression was seen versus placebo and control
hearts. Endothelial dysfunction in isolated aortic
rings from control and placebo-treated SHR was significantly improved
by ACE inhibition and associated with enhanced NO release. Late
treatment of SHR with the ACE inhibitor ramipril extended
lifespan from 21 to 30 months, which is comparable to the lifespan of
untreated normotensive Wistar-Kyoto rats. This lifespan extension,
probably due to blood pressure reduction, correlated with increased
eNOS expression and activity followed by a regression of left
ventricular hypertrophy and cardiac and
vascular dysfunction.
Key Words: ramipril • cardiac function • hypertrophy • endothelium • rats, inbred SHR • nitric-oxide synthase, endothelial
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