(Hypertension. 2000;35:908.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Long-Term Angiotensin II Type 1 Receptor Blockade With Fonsartan Doubles Lifespan of Hypertensive Rats
From Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, Frankfurt/Main, Germany.
Correspondence to Dr Wolfgang Linz, Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases (H813), D-65926 Frankfurt/Main, Germany. E-mail Wolfgang.Linz{at}aventis.com
Abstract— In this study, we
investigated the outcome of lifelong treatment with the
angiotensin II type 1 receptor (AT1) blocker
fonsartan (HR 720) in young stroke-prone spontaneously hypertensive
rats (SHR-SP). In addition to the primary 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/activity of
endothelial nitric oxide synthase and of
angiotensin-converting enzyme (ACE) were also investigated.
Ninety 1-month-old SHR-SP were allotted to 2 groups and treated via
drinking water with an antihypertensive dose of fonsartan (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 normotensive Wistar-Kyoto rats. After 15 months, a time
when 
80% of the placebo group had died, left
ventricular hypertrophy was completely
prevented in fonsartan-treated animals. Furthermore, cardiac function
and metabolism as well as endothelial
function were significantly improved. These effects were correlated
with increased endothelial nitric oxide synthase
expression in the heart and carotid artery and with markedly decreased
tissue ACE expression/activities. Lifespan extension and
cardiovascular protection by long-term AT1
blockade with fonsartan led to similar beneficial effects, as observed
with long-term ACE inhibition.
Key Words: angiotensin II • angiotensin-converting enzyme • fonsartan • nitric oxide synthase • rats, stroke-prone spontaneously hypertensive
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