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Effect of long-term ACE inhibition on myocardial tissue in hypertensive stroke-prone rats
R Zimmermann1, J Kastens, W Linz
1Kerckhoff-Clinic GmbH, Department of Experimental Cardiology, Bad Nauheim, Germany.
Insights
Long-term ramipril treatment in spontaneously hypertensive stroke-prone rats (SHR-SP) prevented myocardial hypertrophy and cardiac damage. High-dose ramipril inhibited cardiac fibrosis and necrosis, extending lifespan.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Spontaneously hypertensive stroke-prone rats (SHR-SP) are a model for studying hypertension-induced cardiac damage.
- Myocardial hypertrophy and fibrosis are key pathological features in hypertensive heart disease.
Purpose of the Study:
- To investigate the long-term effects of ramipril, an ACE inhibitor, on myocardial hypertrophy and its molecular mechanisms in SHR-SP.
- To determine if anti-hypertensive versus non-anti-hypertensive doses of ramipril differentially impact cardiac remodeling.
Main Methods:
- Lifelong administration of ramipril (high and low doses) or placebo to pre-hypertensive SHR-SP.
- Cardiac tissue analysis after 15 months using immunohistochemistry and Northern blot.
- Assessment of structural proteins, extracellular matrix proteins, and growth factors.
Main Results:
- High-dose ramipril (RHI) prevented myocyte hypertrophy (ANP) and cardiac degeneration, loss of structural proteins (alpha-actinin), inflammation (CD45), and extracellular matrix deposition (collagen, fibronectin, vimentin).
- RHI downregulated TGF-β1, collagen α1(I), and fibronectin mRNA levels compared to placebo.
- Vascular Endothelial Growth Factor (VEGF) mRNA levels increased in both ramipril groups.
Conclusions:
- Long-term, high-dose ramipril prevents cardiac hypertrophy, necrosis, and fibrosis in SHR-SP, correlating with life extension.
- The anti-fibrotic and anti-necrotic effects appear independent of VEGF modulation.
Abstract:
The aim of the study was to investigate the influence of long-term ACE inhibition with ramipril on myocardial hypertrophy and its molecular background in spontaneously hypertensive stroke-prone rats (SHR-SP). Therefore, 1-month-old pre-hypertensive SHR-SP were randomized into three groups and exposed lifelong via drinking water to 1 mg/kg/day ramipril (anti-hypertensive dose, RHI), 10 micrograms/kg/day ramipril (non-anti-hypertensive dose, RLO) or placebo. After 15 months cardiac tissue was collected from ten rats each for immunohistochemistry and Northern blot analysis of structural proteins, proteins of the extracellular matrix and several growth factors. Results showed that RHI, but not RLO, treatment prevented development of myocyte hypertrophy (ANP). Furthermore, unlike placebo-treated rats, the ramipril-treated animals had no evidence of degeneration and loss of structural proteins (alpha -actinin), inflammatory infiltrates (CD45) and deposition of extracellular matrix proteins (collagen, fibronectin, vimentin). Only in RHI-treated animals, mRNA levels for TGF- beta(1)as well as of collagen alpha(1)(I) and fibronectin were downregulated compared to placebo-treated animals. In contrast, VEGF mRNA levels increased significantly in both groups of ramipril-treated animals v. placebo-treated SHR-SP. Thus, the reported life prolonging effect of high doses of ramipril which is associated with prevention of hypertension and hypertrophy is accompanied by prevention of the development of necrosis and fibrosis. The role of VEGF, however, seems to be independent of this effect.