Long-acting calcium channel blocker benidipine suppresses expression of angiogenic growth factors and prevents cardiac remodelling in a Type II diabetic rat model.
OBJECTIVE
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-beta(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- beta(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.


CONCLUSIONS
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.
Jesmin
S
S
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Sakuma
I
I
Hattori
Y
Y
Fujii
S
S
Kitabatake
A
A
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D008222:Lymphokines / Q000235:genetics; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C061004:benidipine; D003094:Collagen; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat