Endothelin and Free Radicals Modulate Microvascular Responses in Streptozotocin-Induced Diabetic Rats

doi:10.1006/mvre.1999.2209

Microvascular Research

Volume 59, Issue 1, January 2000, Pages 88-98

https://doi.org/10.1006/mvre.1999.2209 Get rights and content

Abstract

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 muscle-dependent 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 function in diabetes and that their effect could be reversed early in the disease.

References (37)

L.A. Bharadwaj et al.
Mechanism of hydroxyl radical-induced modulation of vascular tone
Free Rad. Biol. Med.
(1997)
R. Gamse et al.
Reduced neurogenic inflammation in streptozotocin-diabetic rats due to microvascular changes but not to substance P depletion
Eur. J. Pharmacol.
(1985)
Y. Hattori et al.
Effects of glucose and insulin on immunoreactive endothelin-1 release from cultured porcine aortic endothelial cells
Metabolism
(1991)
K. Kamata et al.
Functional changes in vascular smooth muscle and endothelium of arteries during diabetes mellitus
Life Sci.
(1992)
Z. Khalil et al.
Sequence of events in substance P-mediated plasma extravasation in rat skin
Brain Res.
(1989)
Z. Khalil et al.
Free radicals contribute to the reduction in peripheral vascular responses and the maintenance of thermal hyperalgesia in rats with chronic construction injury
Pain
(1999)
Z. Khalil et al.
Mechanisms underlying the vascular activity β-amyloid protein fragment (βA₄ 25-35) at level of skin microvasculature
Brain Res.
(1996)
I. Nakamura et al.
Experimental diabetes upregulates the expression of uretereral endothelin receptors
Peptides
(1997)
T. Ohkuwa et al.
Hydroxyl radical formation in diabetic rats induced by streptozotocin
Life Sci.
(1995)
P.A. Rittenhouse et al.
Streptozotocin-induced diabetes is associated with altered expression of peptide-encoding mRNAs in rat sensory neurons
Peptides
(1996)

L. Vesci et al.

Cardiac and renal endothelin-1 binding sites in streptozotocin-induced diabetic rats

Pharmacol. Res.

(1995)

P.V. Andrews et al.

NK1 receptor mediation of neurogenic plasma extravasation in rat skin

Br. J. Pharmacol.

(1989)

C.R.W. Bell et al.

The density and distribution of endotehlin-1 and endothelin receptor subtypes in normal and diabetic rat corpus cavenosum

Br. J. Urol.

(1995)

G.S. Bennett et al.

Neurogenic cutaneous vasodilatation and plasma extravasation in diabetic rats: Effect of insulin and nerve growth factor

Br. J. Pharmacol.

(1998)

D. Diederich et al.

Endothelial dysfunction in mesenteric arteries of diabetic rats: Role of free radicals

Am. J. Physiol.

(1994)

R.M. Edwards et al.

Characterization of 125l-endothelin-1 binding to rat and rabbit renal microvasculature

J. Pharmacol. Exp. Ther.

(1995)

L.E. Franzen et al.

Impaired connective tissue repair in streptozotocin-induced diabetes shows ultrastructural signs of impaired contraction

J. Surg. Res.

(1995)

D. Giugliano et al.

oxidative stress and diabetic vascular complications

Diabetes Care

(1996)

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Sprague–Dawley rats (130–170 g) were injected with streptozotocin (75 mg/kg, ip) and treated with daily aminoguanidine (AG, 25 mg/kg, ip) or vehicle for 2 or 4 weeks.
The base of a vacuum-induced blister raised on the hind paw was perfused with substance P (SP, 1 μM) and sodium nitroprusside (SNP, 100 μM). Changes in blood flow and plasma extravasation (PE) were measured. Amadori (1 mg/ml), advanced glycation end products (AGEs, 10 mg/ml), and anti-RAGE IgG (antibody against AGE receptors, 100 μg/ml) were individually perfused prior to SP.
In diabetic rats, responses to SNP and SP were reduced by 60% and 70%, respectively (P<.05). Amadori increased responses to SNP by 50% and 90% and to SP by 70% and 80% in control and diabetic rats, respectively (both P<.05). SP responses were significantly increased after anti-RAGE IgG (70%) or AG treatments (175%) with PE responses normalized.
Amadori and anti-AGE agents enhance peripheral vascular responses in diabetes and may ameliorate microvascular damage.
Influence of Helicteres isora administration for diabetes mellitus: The effect on changes in tissue fatty acid composition
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This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).
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This paper plagiarized part of papers that had already appeared in: Elevated expression of αA- and αB-crystallins in streptozotocin-induced diabetic rat. P. Anil Kumara, Abdul Haseeba, P. Suryanarayanaa, Nasreen Z. Ehteshama and G. Bhanuprakash Reddy, Arch. Biochem. Biophys., 444 (2005) 77–83; Essential fatty acids in health and disease. Das, U.N., J. Assoc. Physicians India, 47 (1999) 906–911; Protective Role of Phaseolus vulgaris on Changes in the Fatty Acid Composition in Experimental Diabetes. Leelavinothan Pari, Subramanian Venkateswaran, J. Med. Food, 7 (2004) 204–209, doi:10.1089/1096620041224120; Fatty acid composition of erythrocyte phospholipids is related to insulin levels, secretion and resistance in obese type 2 diabetics on Metformin. Yanik Rodríguez Enriqueza, Mimi Girib, Raoul Rottiersb and Armand Christophe, Clin. Chim. Acta, 346 (2004) 145–152; Cytotoxic Activity of Amorphophallus paeoniifolius Tuber Extracts In vitro. J. Angayarkannai, K.M Ramkumar, T. Poornima and U. Priyahdarshini, Am.-Eurasian J. Agric. Environ. Sci., 2 (2007) 395–398; Protective role of tetrahydrocurcumin on changes in the fatty acid composition in streptozotocin-nicotinamide induced type 2 diabetic rats. Pidaran Murugan, Leelavinothan Pari, J. Appl. Biomed., 5 (2007) 31–38.
One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.
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Oxidative stress has been suggested to be a contributory factor in development and complication of diabetes. In the present study, we have investigated the effect of tetrahydrocurcumin (THC), one of the active metabolites of curcumin on antioxidants status in streptozotocin–nicotinamide induced diabetic rats. Oral administration of THC at 80 mg/kg body weight of diabetic rats for 45 days resulted in significant reduction in blood glucose and significant increase in plasma insulin levels. In addition, THC caused significant increase in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, reduced glutathione, vitamin C and vitamin E in liver and kidney of diabetic rats with significant decrease in thiobarbituric acid reactive substances (TBARS) and hydroperoxides formation in liver and kidney, suggesting its role in protection against lipid peroxidation induced membrane damage. These biochemical observations were supplemented by histopathological examination of liver and kidney section. The antidiabetic and antioxidant effects of THC are more potent than those of curcumin at the same dose. Results of the present study indicated that THC showed antioxidant effect in addition to its antidiabetic effect in type 2 diabetic rats.
Effect of an 8-week resistance training program on cutaneous perfusion in type 2 diabetes
2006, Microvascular Research
A positive association has previously been demonstrated between chronic aerobic exercise and prior maximal exercise and enhanced dorsal foot skin perfusion in physically active individuals with type 2 diabetes. The current study examined whether an 8-week resistance training program would also positively affect cutaneous perfusion in type 2 diabetic individuals. Ten individuals with type 2 diabetes and nine similar nondiabetic controls participated in 8 weeks of moderate-intensity resistance training. Prior to training, dorsal foot cutaneous perfusion was measured noninvasively by continuous laser Doppler assessment at baseline and during localized heating to 44°C. These measurements were repeated exactly 48–72 h following 8 weeks of resistance training performed 3 days per week. Interstitial nitric oxide (NO) levels were measured concurrently in the contralateral foot dorsum. Neither subject group experienced significant increases in dorsal foot perfusion responsiveness during local heating to 44°C following moderate resistance training, nor did the training significantly enhance baseline skin perfusion. Interstitial NO levels were not significantly different under any condition. At baseline, groups differed only on fasting serum glucose and overall glycemic control. In conclusion, the responsiveness of cutaneous perfusion in response to heating to 44°C is not significantly enhanced by 8 weeks of moderate resistance training in diabetic individuals or their matched controls, independent of interstitial NO levels.
The effect of N-acetylcysteine on cardiac contractility to dobutamine in rats with streptozotocin-induced diabetes
2005, European Journal of Pharmacology
Citation Excerpt :
Chronic treatment of alloxan-induced diabetic mice with N-acetylcysteine reduced the activation of the nuclear transcription factor-κB in the pancreas, and this has the potential of reducing the production of proinflammatory cytokines such as interleukins and inducible nitric oxide synthase (Ho et al., 1999). Acute administration of N-acetylcysteine also improved vasodilatation response to electrical stimulation or to substance P in rats with streptozotocin-induced diabetes (Bassirat and Khalil, 2000). Chronic treatment with N-acetylcysteine prevented the development of peripheral neuropathy in streptozotocin-induced diabetic rats (Sagara et al., 1996), as well as ultrastructure changes in the erythrocytes of patients with type II diabetes (Straface et al., 2002).
We examined if myocardial depression at the acute phase of diabetes (3 weeks after injection of streptozotocin, 60 mg/kg i.v.) is due to activation of inducible nitric oxide synthase and production of peroxynitrite, and if treatment with N-acetylcysteine (1.2 g/day/kg for 3 weeks, antioxidant) improves cardiac function. Four groups of rats were used: control, N-acetylcysteine-treated control, diabetic and N-acetylcysteine-treated diabetic. Pentobarbital-anaesthetized diabetic rats, relative to the controls, had reduced left ventricular contractility to dobutamine (1–57 μg/min/kg). The diabetic rats also had increased myocardial levels of thiobarbituric acid reactive substances, immunostaining of inducible nitric oxide synthase and nitrotyrosine, and similar baseline 15-F_2t-isoprostane. N-acetylcysteine did not affect responses in the control rats; but increased cardiac contractility to dobutamine, reduced myocardial immunostaining of inducible nitric oxide synthase and nitrotyrosine and level of 15-F_2t-isoprostane, and increased cardiac contractility to dobutamine in the diabetic rats. Antioxidant supplementation in diabetes reduces oxidative stress and improves cardiac function.
Change in cutaneous perfusion following 10 weeks of aerobic training in Type 2 diabetes
2005, Journal of Diabetes and its Complications
A small, but positive, association between aerobic training status or prior maximal exercise and enhanced dorsal foot skin perfusion in active individuals with Type 2 diabetes has been shown. This study, therefore, was designed to examine whether an aerobic training intervention would positively affect cutaneous perfusion in sedentary Type 2 diabetic individuals as well. Nine sedentary participants with Type 2 diabetes (DS) and 10 obese nondiabetic controls (CS) were studied. Prior to the initiation of aerobic training, dorsal foot cutaneous perfusion was measured noninvasively by continuous laser Doppler assessment at baseline and during localized heating to 44 °C. These measurements were repeated 48–72 h following 10 weeks of moderate aerobic training performed 3 days per week. Interstitial nitric oxide (NO) levels were measured concurrently in the contralateral foot dorsum. Aerobic training did not significantly enhance baseline skin perfusion, nor were interstitial NO levels different under any condition. At baseline, groups differed only in glycated hemoglobin (HbA1c), fasting serum glucose, HDL-cholesterol, and insulin resistance. At rest, cutaneous perfusion during local heating to 44 °C was significantly lower in DS before training, but did not differ significantly from CS afterward. Neither group, however, experienced significant increases in dorsal foot perfusion during local responsiveness to heating to 44 °C following 10 weeks of moderate aerobic training, despite slightly lower perfusion in DS before training; these findings were independent of interstitial NO levels. Thus, moderate aerobic training for only 10 weeks does not appear to reverse the impairment in cutaneous perfusion of the foot dorsum in response local heating in a Type 2 diabetic population.

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Regular ArticleEndothelin and Free Radicals Modulate Microvascular Responses in Streptozotocin-Induced Diabetic Rats

Abstract

Free Rad. Biol. Med.

Eur. J. Pharmacol.

Metabolism

Life Sci.

Brain Res.

Pain

Brain Res.

Peptides

Life Sci.

Peptides

Pharmacol. Res.

NK1 receptor mediation of neurogenic plasma extravasation in rat skin

Br. J. Pharmacol.

The density and distribution of endotehlin-1 and endothelin receptor subtypes in normal and diabetic rat corpus cavenosum

Br. J. Urol.

Neurogenic cutaneous vasodilatation and plasma extravasation in diabetic rats: Effect of insulin and nerve growth factor

Br. J. Pharmacol.

Endothelial dysfunction in mesenteric arteries of diabetic rats: Role of free radicals

Am. J. Physiol.

Characterization of 125l-endothelin-1 binding to rat and rabbit renal microvasculature

J. Pharmacol. Exp. Ther.

Impaired connective tissue repair in streptozotocin-induced diabetes shows ultrastructural signs of impaired contraction

J. Surg. Res.

oxidative stress and diabetic vascular complications

Diabetes Care

Regular Article
Endothelin and Free Radicals Modulate Microvascular Responses in Streptozotocin-Induced Diabetic Rats