Late treatment with ramipril increases survival in old spontaneously hypertensive rats.
Spontaneously hypertensive rats (SHR) begin to die from cardiovascular complications at approximately 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 approximately 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.
Linz
W
W
Hoechst Marion Roussel, DG Cardiovascular Diseases, Frankfurt/Main, Germany. wolfgang.linz@hmrag.com
Wohlfart
P
P
Schoelkens
B A
BA
Becker
R H
RH
Malinski
T
T
Wiemer
G
G
D000367:Age Factors; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight; D006332:Cardiomegaly / Q000150:complications; D003627:Data Interpretation, Statistical; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000401:mortality*; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D010919:Placebos; D017257:Ramipril / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000032:analysis; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D010919:Placebos; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D017257:Ramipril