Cardiac and renal endothelin-1 binding sites in streptozotocin-induced diabetic rats (original) (raw)
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Endothelium-journal of Endothelial Cell Research, 2005
This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ET A -Rs/ET B -Rs, at the coronary endothelium (CE) and cardiomyocyte (CM) sites. It is carried out in normal and normotensive rats with streptozotocininduced diabetes mellitus receiving different treatment modalities. Normal rats were divided into two groups, namely a placebo (N) and a losartan-treated (NL), and diabetic rats into four groups receiving placebo (D), insulin-treated (DI), losartan-treated (DL), and insulin/losartan-treated (DIL) respectively. Binding kinetics of ET-1 to ET A -Rs/ET B -Rs on CE and CMs were assessed in the above groups to try to explain the effect of therapeutic doses of an angiotensin II receptor subtype-1 blocker on the dynamics of this ligand and its receptor in insulin supplemented diabetic animals. Each group was divided into two subgroups: CHAPS-untreated and CHAPS-treated rat hearts perfused with [ 125 I]ET-1 to respectively estimate ET-1 binding affinity (τ = 1/k −n ) to its receptor subtype(s) on CE and CMs using mathematical modeling describing a 1:1 reversible binding stoichiometry. Heart perfusion results revealed that insulin treatment significantly decreased τ on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in τ value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized τ on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ET A -R density in all diabetic groups. However, significant decrease in ET B -R density was observed in all groups compared to the normal, and was reconfirmed by immunohistochemical analysis. In conclusion, coadministration of insulin and losartan in nonhypertensive animals suffering from diabetes type 1 may offer new cardiac protection benefits by improving coronary 225 Endothelium Downloaded from informahealthcare.com by American University of Beirut on 06/24/14
Diabetes-induced myocardial structural changes: role of endothelin-1 and its receptors
Journal of Molecular and …, 2000
S. C, T. E, K. M, M. K S. C. Diabetes-induced Myocardial Structural Changes: Role of Endothelin-1 and its Receptors. Journal of Molecular and Cellular Cardiology (2000) 32, 1621-1629. Several metabolic abnormalities may be triggered secondary to hyperglycemia in diabetes. Some of these abnormalities may alter expression of vasoactive factors in the target organs of diabetic complications. We investigated alterations of endothelin-1 (ET-1) and its receptors, ET A and ET B , and associated structural changes in the myocardium of streptozotocin-induced diabetic rats after 6 months of hyperglycemia. We further assessed the preventive effects of an ET-receptor antagonist bosentan∇ on these changes. Compared to the non-diabetic, age-and sex-matched control animals, diabetic rats showed hyperglycemia, glucosuria, reduced body weight gain and elevated glycated Hb levels. Measurement of ET-1, ET A and ET B mRNAs by semiquantitative RT-PCR showed significantly increased mRNA levels in the hearts of diabetic rats. Treatment with bosentan∇ failed to reduce ET-1 or ET B mRNA expression in diabetes, however ET A mRNA expression was reduced. Immunocytochemically, ET-1 was detected in the cardiomyocytes, endothelium and smooth muscle cells of the larger blood vessels and was increased in diabetes. Autoradiographic localization of ET-1 receptors, using 125 I-ET-1, showed increased binding in the endothelium and myocardium of diabetic animals. Histologically, focal fibrous scarring with apoptotic cardiomyocytes, consistent with changes secondary to microvascular occlusion, was only present in the diabetic rats. In keeping with focal fibrosis, myocardium from diabetic rats further showed significantly increased mRNA expression of two extracellular matrix protein transcripts, fibronectin and collagen 1(IV) which were completely prevented by treatment with bosentan∇.
Life sciences, 2014
The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels. Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump. The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA...
Diabetologia, 2011
Aims/hypothesis Activation of endothelin receptor-A (ET A ) increases glomerular permeability to albumin (P alb ) and elevates pro-inflammatory markers in hyperglycaemic rats. Methods Male Sprague-Dawley rats were given streptozotocin (n=32) or saline (sham; n=32). Half of the animals in each group received the ET A -selective antagonist, ABT-627 (atrasentan; orally), beginning immediately after hyperglycaemia was confirmed. Glomeruli were isolated by sieving techniques and P alb determined from the change in glomerular volume induced by oncotic gradients of albumin. Glomerular nephrin levels were assessed by immunofluorescence, whereas urinary nephrin was measured by immunoassay.
Alteration of endothelins: a common pathogenetic mechanism in chronic diabetic complications
Experimental …, 2002
Endothelin (ET) peptides perform several physiological, vascular, and nonvascular functions and are widely distributed in a number of tissues. They are altered in several disease processes including diabetes. Alteration of ETs have been demonstrated in organs of chronic diabetic complications in both experimental and clinical studies. The majority of the effects of ET alteration in diabetes are due to altered vascular function. Furthermore, ET antagonists have been shown to prevent structural and functional changes induced by diabetes in animal models. This review discusses the contribution of ETs in the pathogenesis and the potential role of ET antagonism in the treatment of chronic diabetic complications.
Journal of Cardiovascular Pharmacology, 2004
Type I diabetes is associated with vascular endothelial abnormalities. Vasoactive mediators such as endothelins and reactive oxygen species are modulated in diabetic patients. We studied the hemodynamic profile and the release of mediators alongside the onset of streptozotocin-induced type I diabetes in rats. Arterial plasma samples were collected from chronically instrumented, unrestrained and conscious normotensive versus streptozotocin-diabetic rats. Streptozotocin-diabetic rats developed severe hypoinsulinemia and subsequent hyperglycemia within 5 days. Mean arterial blood pressure and heart rate decreased from 107 to 87 mmHg (19%) and from 386 to 282 beats per minute (bpm) (27%), respectively over 21 days. On day 20 post-streptozotocin administration, markers of oxidative stress (reactive oxygen species: hydrogen peroxide, total peroxides) and related vasodilatory nitric oxide metabolites, increased. Plasma concentrations of atrial natriuretic peptide were not affected, while vasocontractile endothelin-1 and big endothelin-1 increased in streptozotocindiabetic rats versus chronically instrumented, unrestrained and conscious normotensive rats. In addition, the ratios of endothelin-1 : big endothelin-1 and nitric oxide : endothelin-1 were increased. The depressed hemodynamic profile may result from an imbalance between vasocontracting and relaxing factors. Their interactions with reactive oxygen species may affect vascular tone and lead to vascular complications prevalent in this pathological condition. Defining the complex regulation and roles of these factors merits further investigations, especially in the later endstages of vascular complications, because the development of these complications is linked to the duration of the diabetic state.
Role of Endothelin in Diabetic Vascular Complications
Endocrine, 2001
Endothelin-1 (ET-1), a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells, is recognized as a product of many other cells as well. It is now known that there are three endothelin genes in the human genome (ET-1, ET-2, and ET-3). ET-1 and ET-2 are both strong vasoconstrictors, whereas ET-3 is a potentially weaker vasoconstrictor than the other two isoforms. Besides being the most potent vasoconstrictor yet known, ET-1 also acts as a mitogen on the vascular smooth muscle, and, thus, it may play a role in the development of vascular diseases. It is well known that accelerated angiopathy is a major complication in diabetes mellitus. As generalized endothelial cell damage is thought to occur in diabetic patients, ET-1, being released from the damaged endothelial cells, is able to make contact with the underlying vascular smooth muscle cells and thus could be one important cause of diabetic angiopathy. This article summarizes the reported literature of the role of ET-1 in the development of diabetic complications, with particular focus on the possible role of ET-1 in mediating the effects of angiotensin-converting enzyme inhibitors.
Effects of transgenic endothelin-2 overexpression on diabetic cardiomyopathy in rats
European Journal of Clinical Investigation, 2010
Eur J Clin Invest 2010; 40 (3): 203–210Eur J Clin Invest 2010; 40 (3): 203–210AbstractBackground Transgenic overexpression of human endothelin-2 in rats was used to characterize the contribution of endothelin to diabetic cardiomyopathy.Materials and methods Diabetes mellitus was induced by streptozotocin in transgenic rats and transgene-negative controls. Nondiabetic animals were included as well to form a 4-group study design. Heart morphological and molecular alterations were analysed following 6 months of hyperglycaemia.Results Plasma endothelin concentrations were significantly higher in both transgenic groups than in wild-type groups (nondiabetic: 3·5 ± 0·4 vs. 2·1 ± 0·2, P < 0·05; diabetic: 4·5 ± 0·4 vs. 2·5 ± 0·4 fmol mL−1, P < 0·01). Diabetes induced cardiac hypertrophy in both wild-type and transgenic rats and showed the highest myocardial interstitial tissue volume density in diabetic transgenic rats (1·5 ± 0·07%) as compared with nondiabetic transgenic (1·1 ± 0·03%), nondiabetic wild-type (0·8 ± 0·01%) and diabetic wild-type rats (1·1 ± 0·03%; P < 0·01 for all comparisons). A similar pattern with the most severe changes in the enothelin-2 transgenic, diabetic animals was observed for hypertrophy of the large coronary arteries and the small intramyocardial arterioles respectively. Cardiac mRNA expression of endothelin-1, endothelin receptors type A and B were altered in some degree by diabetes or transgenic overexpression of endothelin-2, but not in a uniform manner. Blood pressure did not differ between any of the four groups.Conclusions Overexpression of the human endothelin-2 gene in rats aggravates diabetic cardiomyopathy by more severe coronary and intramyocardial vessel hypertrophy and myocardial interstitial fibrosis. This transgenic intervention provides further and independent support for a detrimental, blood pressure-independent role of endothelins in diabetic cardiac changes.Background Transgenic overexpression of human endothelin-2 in rats was used to characterize the contribution of endothelin to diabetic cardiomyopathy.Materials and methods Diabetes mellitus was induced by streptozotocin in transgenic rats and transgene-negative controls. Nondiabetic animals were included as well to form a 4-group study design. Heart morphological and molecular alterations were analysed following 6 months of hyperglycaemia.Results Plasma endothelin concentrations were significantly higher in both transgenic groups than in wild-type groups (nondiabetic: 3·5 ± 0·4 vs. 2·1 ± 0·2, P < 0·05; diabetic: 4·5 ± 0·4 vs. 2·5 ± 0·4 fmol mL−1, P < 0·01). Diabetes induced cardiac hypertrophy in both wild-type and transgenic rats and showed the highest myocardial interstitial tissue volume density in diabetic transgenic rats (1·5 ± 0·07%) as compared with nondiabetic transgenic (1·1 ± 0·03%), nondiabetic wild-type (0·8 ± 0·01%) and diabetic wild-type rats (1·1 ± 0·03%; P < 0·01 for all comparisons). A similar pattern with the most severe changes in the enothelin-2 transgenic, diabetic animals was observed for hypertrophy of the large coronary arteries and the small intramyocardial arterioles respectively. Cardiac mRNA expression of endothelin-1, endothelin receptors type A and B were altered in some degree by diabetes or transgenic overexpression of endothelin-2, but not in a uniform manner. Blood pressure did not differ between any of the four groups.Conclusions Overexpression of the human endothelin-2 gene in rats aggravates diabetic cardiomyopathy by more severe coronary and intramyocardial vessel hypertrophy and myocardial interstitial fibrosis. This transgenic intervention provides further and independent support for a detrimental, blood pressure-independent role of endothelins in diabetic cardiac changes.
Endothelins in chronic diabetic complications
Canadian journal of physiology and …, 2003
Endothelins are widely distributed in the body and perform several vascular and nonvascular functions. Experimental data indicate abnormalities of the endothelin system in several organs affected in chronic diabetic complications. In support of this notion, it has been shown that endothelin-receptor antagonists prevent structural and functional abnormalities in target organs of diabetic complications in animal models. Alterations of plasma endothelin levels have also been demonstrated in human diabetes. This review discusses the role of endothelins in the pathogenesis of chronic diabetic complications. The current experimental evidence suggests that endothelin-receptor antagonism may potentially be an adjuvant therapeutic tool in the treatment of chronic diabetic complications.