Insulin and vanadate restore decreased plasma endothelin concentrations and exaggerated vascular responses to normal in the streptozotocin diabetic rat (original) (raw)
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Diabetologia, 1994
Abnormal vascular endothelium function may contribute to the reduced nerve perfusion implicated in the aetiology of neuropathy in diabetes mellitus. The aim was to test the hypothesis that a powerful vasoconstrictor, endothelin-1, could be involved in nerve dysfunction in streptozotocin-diabetic rats. After 6 weeks of untreated diabetes, rats were implanted with osmotic minipumps which continuously delivered the endothelin-1 antagonist, BQ-123, to the circulation via a jugular vein cannula. Sciatic motor conduction velocity, monitored serially, was increased after 4 days, treatment (p = 0.028), and reached asymptote by 9-11 days (p = 0.0001), when the degree of amelioration was approximately 60 % of the initial diabetic deficit. Treatment of non-diabetic rats for 13 days with BQ-123 had no significant effect on motor conduction velocity. Sensory saphenous nerve conduction velocity was measured acutely after 20 days, BQ-123 treatment. The amelioration of a sensory deficit was approximately 80 % (p < 0.001); the resultant conduction velocity value was not significantly different from that of a non-diabetic control group. After 20 days, treatment, sciatic nutritive endoneurial blood flow was measured by microelectrode polarography and hydrogen clearance. A 48 % deficit with untreated diabetes (p < 0.001) was 64 % ameliorated by BQ-123 treatment (p < 0.001). In non-diabetic rats, BQ-123 treatment had no effect on blood flow. We conclude that endothelin-1 does not seem to be involved in the control of nerve blood flow in non-diabetic rats; however, it makes a major contribution to the perfusion deficit in experimental diabetes. This has deleterious consequences for nerve conduction, and it is possible that endothelin-1 receptor blockade may have therapeutic potential in diabetic patients.
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.
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.
Endothelin Antagonism Uncovers Insulin-Mediated Vasorelaxation In Vitro and In Vivo
Hypertension, 2001
The endothelial actions of insulin remain an area of intense research because they relate to both insulin sensitivity and vascular tone. Physiological doses of insulin evoke endothelium-dependent vasorelaxation in humans; however, this remains a pharmacological phenomenon in rat aortas. Because insulin may stimulate the divergent production of both nitric oxide and endothelin-1, we hypothesized that the lack of insulin-induced vasorelaxation at low/subthreshold concentrations may be due to the concurrent production of endothelin-1, which in turn serves to inhibit nitric oxide-dependent, insulin-mediated dilation. To investigate this, we studied the effects of subthreshold concentrations of insulin (100 mU/L) on norepinephrine-induced contraction in rat aortas following short-term and long-term endothelin blockade. In addition, the effects of tetrahydrobiopterin inhibition (with diaminohydroxyprimidine) on norepinephrine-induced contraction in the presence of insulin and endothelin r...
Cardiac and renal endothelin-1 binding sites in streptozotocin-induced diabetic rats
Pharmacological Research, 1995
The aim of this work was to study cardiac and renal endothelin binding sites during the progression of diabetes. Male Crl:CD (BR) rats were made diabetic by injection of streptozotocin (STZ, 45 mg kg-t i.v.). Only rats with a glycaemia of 500 mg per 100 ml or higher, were used. The hearts were taken at 2, 4 or 6 weeks and kidneys at 2 and 6 weeks, after diabetes induction, for binding studies. In the heart, the number of Et-1 binding sites was significantly increased 2 weeks after STZ-induction of diabetes (449+13 vs. 345+18 fmol (mg protein)-I, in controls; p<0.05) without modification of Ko value (104+5 vs 101+7 pM). Comparable results were obtained 4 and 6 weeks after STZ-induction. In the kidney both the parameters were unchanged at all the times tested. In conclusion: a specific increase in cardiac Et-1 binding sites, without change in affinity of the peptide, was found 2, 4 and 6 weeks after diabetes induction; while renal Et-I binding sites were not modified.
Microvascular Research, 2000
The quantitative contribution of endothelin and free radicals in modulating peripheral endothelial and smooth muscle-dependent vascular responses in 4 weeks streptozotocin-induced diabetic rats was investigated. Skin blood flow was monitored in base of blisters raised on the hind footpad. Smooth muscledependent vasodilation was tested using sodium nitroprusside (SNP). Endothelial-mediated inflammatory responses were induced via either electrical stimulation (ES) of the sciatic nerve or substance P (SP) perfusion over the blister base. Role of endothelin and free radicals was examined using ET-A or ET-B receptor antagonists (BQ-123 or BQ-788) and superoxide anions or hydroxyl radicals scavengers (superoxide dismutase (SOD) or N-acetyl cysteine (NAC)). Diabetic rats showed a significant reduction (75%) in SNP responses that coincided with a 70 and 60% reduction in responses to ES and SP. Their basal plasma extravasation (PE) was significantly higher while PE response to SP was significantly reduced. BQ-788, was more potent than BQ-123, improving responses to ES and SP in diabetic rats by 85%. Likewise, NAC was more potent than SOD normalizing the ES response and improving SP response by 85%. Combined treatment with BQ-123 and SOD normalized all vasodilatation responses in diabetic rats. BQ-123 and BQ-788 were equally potent normalizing the PE responses to SP whereas SOD and NAC had no effect. We conclude that endothelin and free radicals play a role in altering microvascular func-tion in diabetes and that their effect could be reversed early in the disease.
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.
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.