Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan of hypertensive rats.
In this study, we investigated the outcome of lifelong treatment with the angiotensin II type 1 receptor (AT(1)) 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 approximately 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 AT(1) blockade with fonsartan led to similar beneficial effects, as observed with long-term ACE inhibition.
Linz
W
W
ventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, Frankfurt/Main, Germany. Wolfgang.Linz@aventis.com
Heitsch
H
H
Schölkens
B A
BA
Wiemer
G
G
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008136:Longevity / Q000187:drug effects; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011945:Receptors, Angiotensin / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; C094626:fonsartan