Long-acting calcium channel blocker benidipine suppresses expression of angiogenic growth factors and prevents cardiac remodelling in a Type II diabetic rat model |
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Authors: | S Jesmin I Sakuma Y Hattori S Fujii A Kitabatake |
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Institution: | (1) Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan, JP;(2) Department of Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan, JP |
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Abstract: | Aims/hypothesis: Calcium channel blockers, widely used for the treatment of hypertension and angina, could prevent cardiovascular complications
in patients with diabetes. They can improve cardiac remodelling in animal models of a variety of cardiovascular diseases.
Here, we examined the therapeutic effect of benidipine, a long-acting calcium channel blocker, on cardiac remodelling in Otsuka-Long-Evans-Tokushima-Fatty
(OLETF) rats, a Type II (non-insulin-dependent) diabetes mellitus model.
Methods: The methods for morphometric analysis included double staining for coronary capillaries, dye-binding staining for collagen
content and Masson's trichrome staining for perivascular fibrosis. Immunohistochemical and in situ hybridization techniques
were used for detecting protein and mRNA expressions for vascular endothelial growth factors (VEGF), basic fibroblast growth
factors (bFGF) and TGF-β
1, endothelial nitric oxide synthase (eNOS), and anti- and pro-apoptotic markers.
Results: OLETF rats showed an increased coronary capillary density, a reduced venular capillary proportion, an increased cardiac collagen
content and prominent cardiac perivascular fibrosis. In OLETF rat hearts, significant increases in vascular expressions for
VEGF, bFGF and TGF-β
1 were found. Furthermore, the apoptosis signalling pathways, involving eNOS and apoptotic markers, were markedly altered,
and coronary endothelial cell apoptosis was lower. These alterations with the exception of eNOS expression were significantly
blocked by benidipine treatment.
Conclusion/interpretation: The suppressive effect of benidipine on overproduction of angiogenic growth factors could prevent cardiac angiogenesis and
fibrosis, resulting in an improvement of cardiac remodelling in diabetes. As VEGF and bFGF potently block endothelial cell
apoptosis execution, physiological apoptosis revived by benidipine treatment could also contribute to coronary vessel regression.
Diabetologia (2002) 45: 402–415]
Received: 16 July 2001 and in revised form: 5 November 2001 |
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Keywords: | Type II diabetes mellitus calcium channel blocker coronary capillary network cardiac remodelling angiogenic growth factors coronary endothelial cell apoptosis Otsuka-Long-Evans-Tokushima-Fatty rat |
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