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

Abstract

Aims/hypothesis. 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 (ET A -RB) with that of an ACE-inhibitor (ACE-i) or their combination in rats with Streptozotocin (STZ) diabetes. Methods. 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 ET A -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. Results. ACE-i but not ET A -RB lowered blood pressure in STZ Type 1 diabetic rats. Capillary length density was lower in untreated STZ diabetic rats (2932±128 mm/mm 3 ) compared to non-diabetic control rats (3410±252 mm/mm 3 ). Treatment with ACE-i (3568±431 mm/mm 3 ), but not with ET A -RB (2893±192 mm/mm 3 ), 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%, ET A -RB: 0.7±0.08% and combination: 0.69±0.1). Conclusion/interpretation. 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 ET A -R blockade. A similar trend, although not complete normalisation, was seen in cardiac fibrosis. [Diabetologia (2004) 47:316-324]

Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

“…In addition to the lack of increased myocardial fibrosis, we found no evidence for the cardiomyocyte and arteriolar hypertrophy and reduced myocardial capillary density reported in animal models of diabetes [7,9-11], which may be related to poorer diabetic control in animal models.…”

“…In addition, advanced glycation end-products (AGEs) are proposed to contribute to diabetic cardiomyopathy by cross-linking myocardial proteins such as collagen and elastin, and by promoting collagen accumulation [7]. Evidence for these mechanisms comes mainly from rodent models of diabetes [7-11], and the increased myocardial fibrosis in rodent models has led to the development of genetic models to examine its pathogenesis and to test antifibrotic therapies [8,9]. There is, however, uncertainty about the role of these mechanisms in the human diabetic heart.…”

Renal stem cells: fact or science fiction?

“…Podocyte excretion is dramatically elevated in the setting of many renal diseases, probably reflecting a harmful environment [85]. There are some data suggesting that compensatory podocyte hypertrophy can occur to counteract shedding, and that podocytes hypertrophy in a number of disease states [86–88]; in vitro , podocytes have been observed to undergo hypertrophy in response to glucose and mechanical stretch [89,90]. The observations of podocyte loss and absence of proliferation are at odds with the ability to maintain sufficient podocyte numbers and renal function with age.…”

Metabolic memory: a vascular perspective

“…Induction of inflammatory processes through receptor binding of AGEs or oxidative stress mediate changes of the structure of the extracellular matrix [37]. Subsequent fibrosis and the extension of extracellular structures impair capillary blood flow and in particular reduces capillary density (figure 1) [38-40]. Reduced blood flow may then facilitate microvascular complications.…”