Late Treatment With Ramipril Increases Survival in Old Spontaneously Hypertensive Rats

Abstract

Abstract-Spontaneously hypertensive rats (SHR) begin to die from cardiovascular complications at Ϸ15 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 (nϭ10), placebo-treated (nϭ45), and ramipriltreated with an antihypertensive dose of 1 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 in drinking water (nϭ45). Ex vivo experiments were performed after 15 months (control) and 21 months, when Ϸ80% 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.

Decreased Nitric Oxide Availability in Normotensive and Hypertensive Rats With Failing Hearts After Myocardial Infarction

“…Although in our study sham-operated SHR showed a significantly higher (6-to 7-fold) endothelial O 2 Ϫ production than the respective aortic endothelium of WKY, endotheliumdependent aortic relaxation was slightly greater in SHR than in aortas from sham-operated WKY. A reduced local bioavailability of NO caused by inactivation of NO through O 2 Ϫ despite a normal or even enhanced NO synthesis has been shown in endothelial dysfunction, for example, associated with hypertension, 18 hypercholesterolemia, 27 and high-salt diet. 28 One reason for elevated endothelial O 2 Ϫ formation may be a dysfunctional activity of eNOS.…”

“…Thoracic aorta was taken for evaluation of endothelial function 17 and for determination of NO and O 2 Ϫ production. 18 After evaluation of cardiac functions (contractility, dP/dt max , and aortic flow index, AFI) in the working heart, 18 wet weights of total heart and left and right ventricles were determined.…”

Expression and Response to Angiotensin-Converting Enzyme Inhibition of Matrix Metalloproteinases 2 and 9 in Renal Glomerular Damage in Young Transgenic Rats with Renin-Dependent Hypertension

“…Ren2 rats were randomly assigned to treatment groups at birth. After weaning at the age of 4 weeks, homozygous Ren2 rats were treated until the end of the observation period at 8 weeks of age with the ACE inhibitor ramipril (1 mg/kg/day) in drinking water (Ren2-ramipril) (Aventis Pharma Deutschland GmbH, Frankfurt am Main, Germany) (Linz et al, 1999).…”

Increase in G iα Protein Accompanies Progression of Post-Infarction Remodeling in Hypertensive Cardiomyopathy

“…Each isolated heart was perfused in the working-heart mode with a filling pressure of 15 mm Hg and an afterload pressure of 60 mm Hg, as described previously. 14 After the evaluation of cardiac performance, the heart was weighed, and the LV was sectioned transversely into 4 slices. Photographs were taken from each slice, and the tissues were then snap-frozen in liquid nitrogen and were stored at Ϫ80°C.…”