ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

• Published in: Diabetologia 2004-02, Vol.47 (2), p.316-324
• Main Authors: GROSS, M.-L, HEISS, N, WECKBACH, M, HANSEN, A, EI-SHAKMAK, A, SZABO, A, MÜNTER, K, RITZ, E, AMANN, K
• Format: Article
• Language: English
• Subjects: Albuminuria - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - pathology; Arterioles - drug effects; Arterioles - pathology; Biological and medical sciences; Blood Glucose - analysis; Blood Glucose - drug effects; Blood Glucose - metabolism; Blood pressure; Blood Pressure - drug effects; Blood vessels; Body Weight - drug effects; Cardiomyocytes; Cardiovascular disease; Cardiovascular Diseases - etiology; Cardiovascular Diseases - pathology; Cardiovascular Diseases - prevention & control; Collagen Type IV - analysis; Collagen Type IV - genetics; Coronary vessels; Coronary Vessels - chemistry; Coronary Vessels - drug effects; Coronary Vessels - pathology; Diabetes; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelin A Receptor Antagonists; Endothelin-1 - analysis; Endothelin-1 - genetics; Fibrosis; Gene Expression - drug effects; Heart - drug effects; Heart - physiopathology; Immunohistochemistry; In Situ Hybridization; Indoles - pharmacology; Investigations; Male; Medical sciences; Myocardium - chemistry; Myocardium - pathology; Pathology; Phenylpropionates - pharmacology; Pyrimidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A - analysis; Receptor, Endothelin A - genetics; Smooth muscle; Transforming Growth Factor beta - analysis; Transforming Growth Factor beta - genetics
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-003-1309-z

There is little information whether cardiac capillary supply is deranged in diabetes. Hyperglycaemia is a potent stimulus for endothelin-1 (ET-1) production. We therefore hypothesised that increased ET-1 production in Streptozotocin-induced Type 1 diabetes causes abnormalities of cardiac capillaries and the aorta. To this end we compared the effects of an ET receptor A blocker (ETA-RB) with that of an ACE-inhibitor (ACE-i) or their combination in rats with Streptozotocin (STZ) diabetes. Sprague Dawley rats were injected with 65 mg STZ i.v. and subsequently developed diabetes. Rats were left untreated or received daily either the ACE-i Trandolapril, the ETA-RB Darusentan or a combination of both. After 6 months the experiment was terminated and the heart and the aorta were investigated using quantitative morphological techniques. ACE-i but not ETA-RB lowered blood pressure in STZ Type 1 diabetic rats. Capillary length density was lower in untreated STZ diabetic rats (2932+/-128 mm/mm3) compared to non-diabetic control rats (3410+/-252 mm/mm3). Treatment with ACE-i (3568+/-431 mm/mm3), but not with ETA-RB (2893+/-192 mm/mm3), prevented the decrease in capillary supply. Volume density of the myocardial interstitium was higher in untreated STZ diabetic rats (0.86+/-0.04%) compared to non-diabetic control rats (0.36+/-0.06%). In all three intervention groups the values were lower (ACE-i: 0.53+/-0.05%, ETA-RB: 0.7+/-0.08% and combination: 0.69+/-0.1). Our study identifies a capillary defect of the heart in STZ diabetes, i.e. decreased capillary supply. This abnormality was reversed by ACE-i, but not by ETA-R blockade. A similar trend, although not complete normalisation, was seen in cardiac fibrosis.