Endothelin and Free Radicals Modulate Microvascular Responses in Streptozotocin-Induced Diabetic Rats (original) (raw)
Related papers
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.
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.
Endothelial dysfunction and metabolic control in streptozotocin-induced diabetic rats
British Journal of Pharmacology, 1998
1 The aim of this work was to study the in¯uence of the metabolic control, estimated by the levels of glycosylated haemoglobin in total blood samples (HbA 1c ), in developing vascular endothelial dysfunction in streptozotocin-induced diabetic rats. Four groups of animals with dierent levels of insulin treatment were established, by determining HbA 1c values in 5.5 to 7.4%, 7.5 to 9.4%, 9.5 to 12% and 412%, respectively. 2 The parameters analysed were: (1) the endothelium-dependent relaxations to acetylcholine (ACh) in isolated aorta and mesenteric microvessels; (2) the vasodilator responses to exogenous nitric oxide (NO) in aorta; and (3) the existence of oxidative stress by studying the in¯uence of the free radical scavenger superoxide dismutase (SOD) on the vasodilator responses to both ACh and NO. 3 In both isolated aortic segments and mesenteric microvessels, the endothelium-mediated concentration-dependent relaxant responses elicited by ACh were signi®cantly decreased when the vessels were obtained from diabetic animals but only with HbA 1c values higher than 7.5%. There was a high correlation between HbA 1c levels and the impairment of ACh-induced relaxations, measured by pD 2 values. 4 The concentration-dependent vasorelaxant responses to NO in endothelium-denuded aortic segments were signi®cantly reduced only in vessels from diabetic animals with HbA 1c values higher than 7.5%. Again, a very high correlation was found between the HbA 1c values and pD 2 for NO-evoked responses. 5 In the presence of SOD, the responses to ACh or NO were only increased in the segments from diabetic rats with HbA 1c levels higher than 7.5%, but not in those from non-diabetic or diabetic rats with a good metabolic control (HbA 1c levels 57.5%). 6 These results suggest the existence of: (1) a close relation between the degree of endothelial dysfunction and the metabolic control of diabetes, estimated by the levels of HbA 1c ; and (2) an increased production of superoxide anions in the vascular wall of the diabetic rats, which is also related to the metabolic control of 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.
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.
British Journal of Pharmacology, 2009
Background and purpose: The present experiments were designed to study the contribution of oxygen-derived free radicals to endothelium-dependent contractions in femoral arteries of rats with streptozotocin-induced diabetes. Experimental approach: Rings with and without endothelium were suspended in organ chambers for isometric tension recording. The production of oxygen-derived free radicals in the endothelium was measured with 2 0 ,7 0 -dichlorodihydrofluorescein diacetate using confocal microscopy. The presence of protein was measured by western blotting. Key results: In the presence of L-NAME, the calcium ionophore A23187 induced larger endothelium-dependent contractions in femoral arteries from diabetic rats. Tiron, catalase, deferoxamine and MnTMPyP, but not superoxide dismutase reduced the response, suggesting that oxygen-derived free radicals are involved in the endothelium-dependent contraction. In the presence of L-NAME, A23187 increased the fluorescence signal in femoral arteries from streptozotocin-treated, but not in those from control rats, confirming that the production of oxygen-derived free radicals contributes to the enhanced endotheliumdependent contractions in diabetes. Exogenous H 2 O 2 caused contractions in femoral arterial rings without endothelium which were reduced by deferoxamine, indicating that hydroxyl radicals contract vascular smooth muscle and thus could be an endothelium-derived contracting factor in diabetes. The reduced presence of Mn-SOD and the decreased activity of catalase in femoral arteries from streptozotocin-treated rats demonstrated the presence of a redox abnormality in arteries from rats with diabetes. Conclusions and implications: These findings suggest that the redox abnormality resulting from diabetes increases oxidative stress which facilitates and/or causes endothelium-dependent contractions.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1995
We examined the ability of the oxygen free radical scavenger, BM15.0639 (400 mg kg-1 day-1), to correct existing sciatic motor nerve conduction velocity and endoneurial blood flow deficits in streptozotocindiabetic rats. Rats were treated for 1 month following 1 month of untreated diabetes. Effects of treatment in non-diabetic rats were also examined. A further experiment determined the dose-response relationship for correction of conduction velocity abnormalities by BM15.0639.
Diabetologia, 1993
We examined the potential for some of the abnormalities of vascular endothelium found in diabetes mellitus to cause neuropathic changes. Non-diabetic rats were treated for 2 months with the cyclo-oxygenase inhibitor flurbiprofen (5 rag-kg-1-day 1) to reduce prostacyclin production, the nitric oxide synthase inhibitor N°-nitro-I~-arginine (5 or 25 mg. kg-~. day-l), or combined treatment. There were dosedependent reductions in sciatic motor and saphenous sensory conduction velocity. The two inhibitors acted synergistically, thus, the 5-6 % motor conduction deficits (p < 0.01) produced by either flurbiprofen or N<nitro-L-arginine (5 mg. kg-I. day '1) increased to 17 % (p < 0.001) for combined treatment. With N<nitro-L-arginine (25 mg. kg-1. day-~) and flurbiprofen, motor and sensory conduction velocity were reduced by 23 % (p < 0.001) and 12 % (p < 0.001), respectively, matching the deficits following 2-month streptozotocin diabetes. N<nitro-L-arginine (25 mg-kg-~. day-~) and flurbiprofen together produced a 13 % prolongation of the time taken for 80 % hypoxic conduction failure in vitro (p < 0.05) and a i0 % reduction in sciatic capillary density. A second investigation tested an alternative hypothesis that overproduction of nitric oxide was responsible for vascular-related complications in diabetes, the prediction being that N<nitro-L-arginine (5 mg-kg ~1-day-I) would prevent nerve dysfunction. However, rather than prophylaxis during 2-month streptozotocin diabetes, treatment exacerbated nerve abnormalities. Thus, NQnitro-L-arginine worsened (8%, p < 0.001) the motor conduction deficit, there was an 11% increase in hypoxic conduction failure time (p < 0.01) and an 11% reduction in endoneurial capillary density (p < 0.01). We conclude that overproduction of nitric oxide is unlikely to be involved in the aetiology of experimental diabetic neuropathy. However, endothelial dysfunction resulting in impaired nitric oxide and prostacyclin synthesis could make a substantial contribution.