Prevention by insulin treatment of endothelial dysfunction but not enhanced noradrenaline‐induced contractility in mesenteric resistance arteries from streptozotocin‐induced diabetic rats

Taylor, Paul D.; Oon, Beryl B.; Thomas, Chantal; Poston, Lucilla

doi:10.1111/j.1476-5381.1994.tb14020.x

Cited by 92 publications

(64 citation statements)

References 60 publications

(61 reference statements)

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“…The vascular endothelial dysfunction developed in streptozotocin-induced diabetic rats can be recovered after 8 to 12 weeks of treatment with insulin [51], or with a pancreatic islet transplantation [52]. In these studies, the improvement of endothelial function was accompanied by a parallel improvement in metabolic control, estimated by HbA 1c values [52] or by the extinction of glycosuria or ketonuria [51].…”

Section: Discussionmentioning

confidence: 63%

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

et al. 2003

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Aims/hypothesis. In a model of streptozotocin-induced Type 1 diabetes mellitus in rats of 9 weeks duration, we analysed time associations between the development of hyperglycaemia, early and intermediate glycosylation Amadori adducts, or AGE compared with enhancement of oxidative stress and endothelial dysfunction.Methods. Endothelial function was tested at several stages of streptozotocin-induced diabetes and after treatment with insulin, resulting in different concentrations of blood glucose, glycosylated haemoglobin (an Amadori adduct), and AGE. Other animals were studied antagonising the formation of AGE with aminoguanidine. Results. Relaxation in response to acetylcholine (1 nmol/l to 10 µmol/l) was tested in isolated segments from aorta or mesenteric microvessels. Impairment of endothelium-dependent relaxations occurred after 2 weeks of untreated diabetes. Preincubation of vessels affected with 100 U/ml superoxide dismutase improved the relaxations to acetylcholine, along the time-course of the endothelial impairment. This indicates the participation of reactive oxygen species on diabetic endothelial dysfunction. The impairment of endothelium-dependent relaxations was recovered after 3 more weeks of insulin treatment. Aminoguanidine treatment did not modify this pattern of development. The time course of the rise and disappearance of endothelial dysfunction showed a higher correlation with glycosylated haemoglobin concentrations than with blood glucose or serum AGE. Conclusion/interpretation. Enhancement of early and intermediate Amadori adducts of protein glycosylation was the factor showing a better relation with the development of endothelium impairment. These results are consistent with a role for these products in the development of diabetic vasculopathy. [Diabetologia (2003) 46:556-566] Keywords Diabetes mellitus, endothelial dysfunction, nitric oxide, superoxide anions, hyperglycaemia, Amadori adducts, advanced glycosylation end-products. Endothelial dysfunction seems to be a key factor in the development of diabetic vascular complications. The impairment of endothelium-dependent vasodilatations is an early event occurring in diabetic patients [1,2,3] and animal diabetic models [4,5,6, 7]. Enhanced oxidative stress in diabetes mellitus has been also shown [8,9], which can be detected by peroxidation products [10] or by increased generation of reactive oxygen species (ROS), mainly superoxide anions [11]. Indeed, enhanced oxidative stress is proposed to be a major cause of diabetic endothelial dysfunction [12,13].There is also increasing evidence that diabetic endothelial dysfunction and oxidative stress are a conse-

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Section: Discussionmentioning

confidence: 63%

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

et al. 2003

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“…By contrast, the majority of studies of both large isolated arteries and resistance from rats with chemically-induced diabetes have shown an enhanced senstivity to contractile agents (Harris & MacLeod, 1988;Legan, 1989;Owen & Carrier, 1980;MacLeod & McNeill, 1985;Friedman, 1989;Taylor et al, 1992). Moreover, a study of insulin-treated STZ-induced diabetic rats, showed that insulin did not prevent enhanced contractility to NA, although it did prevent impaired endothelium-dependent relaxation to ACh (Taylor et al, 1994a). These findings contrast with those from human studies, which have shown resistance arteries from insulin dependent diabetis mellitus (IDDM) patients without complications other than background retinopathy, display impaired contractile responses to NA, and impaired endothelium-dependent relaxation to ACh (McNally et al, 1994); furthermore, resistance arteries from healthy volunteers exposed to increasing concentrations of insulin show decreased contractile response to NA in a dose-dependent manner (McNally et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Impaired endothelium‐dependent relaxation in isolated resistance arteries of spontaneously diabetic rats

Heygate

Lawrence

Bennett

et al. 1995

British J Pharmacology

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1 Previous studies have shown that endothelium-dependent relaxation in the aorta of spontaneously diabetic bio bred rats (BB) is impaired. 2 We have investigated noradrenaline (NA) contractility, endothelium-dependent acetylcholine (ACh) and bradykinin (BK) relaxation, and endothelium-independent sodium nitroprusside (SNP) relaxation in mesenteric resistance arteries of recent onset BB rats and established insulin treated BB rats, compared to their age-matched non diabetic controls. 3 There was no significant difference in the maximum contractile response or sensitivity to noradrenaline in either of the diabetic groups compared to their age-matched controls. 4 Incubation with the nitric oxide synthetase inhibitor NG-nitro-L-arginine (L-NOARG) resulted in a significant increase in maximum contractile response to noradrenaline in the recent onset age-matched control group (P<0.05). Analysis of the whole dose-response curve (using ANOVA for repeated measures with paired t test) showed a significant left-ward shift following the addition of L-NOARG (P<0.001). A similar but less marked shift (P<0.01) was evident in vessels from recent onset diabetics. An overall shift in both sensitivity and maximum response was also evident in the age-matched non diabetic controls of the insulin-treated group (P<0.05). However, by contrast, there was no significant change in sensitivity in the insulin-treated diabetic rats. 5 ACh-induced endothelium-dependent relaxation was significantly impaired in the recent onset diabetic rats compared to their age-matched controls (47 ± 11% versus 92 ± 2%, P<0.05, n = 6), and in the insulin treated diabetic rats (34±5% versus 75 + 6%, P< 0.05, n = 6). The relaxation responses to BK also were significantly impaired in the diabetic rats compared to their age-matched controls (recent onset: 20+3% versus 72±7%, P<0.05, n=6; insulin treated: 12+9% versus 68+7%, P<0.05, n=7). 6 Incubation with either the nitric oxide synthetase substrate, L-arginine, or the free radical scavenging enzyme superoxide dismutase (150 jml1') failed to improve the attenuated response of acetylcholineinduced relaxation in the diabetic vessels. 7 Endothelium-dependent relaxation mediated by ACh and BK was significantly attenuated in both the diabetic and control vessels after incubation with L-NOARG. 8 Pretreatment with a cyclo-oxygenase inhibitor, indomethacin, significantly enhanced the relaxation to ACh in both the recent onset and insulin treated diabetic rats (42+10%, n=7 versus 64±7%, n=7, P<0.05, and 40±5%, n=7 versus 65+9%, n=6, P<0.05). 9 Following endothelium removal, there was a marked impairment in endothelium-dependent relaxation responses to ACh and BK in both the diabetic and control vessels. 10 Incubation with the thromboxane A2 receptor antagonist SQ29548, did not significantly improve the ACh endothelium-dependent relaxation response in the diabetic vessels. 11 Endothelium-independent relaxation to sodium nitroprusside was significantly impaired in the first group of diabetic vessels studied; however, subse...

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“…Hyperglycaemia Impaired ACh-induced relaxation was reversed by chronic insulin treatment (Wang et al, 1993;Taylor et al, 1994a), but not by acute insulin administration, even though glycaemia was normalized (Wang et al, 1993;Bucala et al, 1991). Defective endothelium-dependent relaxation was restored 4 weeks after pancreatic transplantation, performed in rats after 12 weeks of diabetes (Pieper et al, 1998a).…”

Section: Aetiology Of Endothelial Dysfunction In Diabetesmentioning

confidence: 99%

Endothelial dysfunction in diabetes

Vriese

Verbeuren

Voorde

et al. 2000

British J Pharmacology

1,009

769

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Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of di erent animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to di er according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.

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Prevention by insulin treatment of endothelial dysfunction but not enhanced noradrenaline‐induced contractility in mesenteric resistance arteries from streptozotocin‐induced diabetic rats

Cited by 92 publications

References 60 publications

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

Impaired endothelium‐dependent relaxation in isolated resistance arteries of spontaneously diabetic rats

Endothelial dysfunction in diabetes

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