Differential effects of ETA and ETB receptor antagonism on oxidative stress in type 2 diabetes

Elgebaly, Mostafa M.; Portik-Dobos, Vera; Sachidanandam, Kamakshi; Rychly, David J.; Malcom, Daniel R.; Johnson, Maribeth H.; Ergul, Adviye

doi:10.1016/j.vph.2007.05.006

Cited by 25 publications

(22 citation statements)

References 36 publications

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“…Although most studies focused on changes observed in the intimal layer mediated by hyperlipidemia and diabetes, the effect of dyslipidemia on the structure and function of the contractile medial layer is not known. We used the type 2 diabetic GK rat, a lean and normotensive model, in combination with diet-induced hyperlipidemia to distinguish the effects of hyperglycemia and high-fat diet either alone or in combination (Cheng et al, 2001;Sachidanandam et al, 2006;Elgebaly et al, 2007). There have been a few reports of remodeling in models of type 1 diabetes (Cooper et al, 1994(Cooper et al, , 1997.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes

Sachidanandam

Hutchinson

Elgebaly³

et al. 2008

J Pharmacol Exp Ther

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Type 2 diabetes and dyslipidemia oftentimes present in combination. However, the relative roles of diabetes and diet-induced dyslipidemia in mediating changes in vascular structure, mechanics, and function are poorly understood. Our hypothesis was that addition of a high-fat diet would exacerbate small artery remodeling, compliance, and vascular dysfunction in type 2 diabetes. Vascular remodeling indices [media/lumen (M/L) ratio, collagen abundance and turnover, and matrix metalloproteinase dynamics], mechanical properties (vessel stiffness), and reactivity to pressure and vasoactive factors were measured in third-order mesenteric arteries in control Wistar and type 2 diabetic Goto-Kakizaki (GK) rats fed either a regular or high-fat diet. M/L ratios, total collagen, and myogenic tone were increased in diabetes. Addition of the high-fat diet altered collagen patterns (mature versus new collagen) in favor of matrix accumulation. Addition of a high-fat diet caused increased constriction to endothelin-1 (0.1-100 nM), showed impaired vasorelaxation to both acetylcholine (0.1 nM-1 M) and sodium nitroprusside (0.1 nM-1 M), and increased cardiovascular risk factors in diabetes. These results suggest that moderate elevations in blood glucose, as seen in our lean GK model of type 2 diabetes, promote resistance artery remodeling resulting in increased medial thickness, whereas addition of a high-fat diet contributes to diabetic vascular disease predominantly by impairing vascular reactivity in the time frame used for this study. Although differential in their vascular effects, both hyperglycemia and diet-induced dyslipidemia need to be targeted for effective prevention and treatment of diabetic vascular disease.It is estimated that over 23 million Americans are affected by type 2 diabetes. Obesity, insulin resistance, and hypertension often cluster along with type 2 diabetes, resulting in a condition known as metabolic syndrome or syndrome X, thus imposing an enormous task from a therapeutic standpoint (Muhammad, 2004). Although studies with obese Zucker rats (Frisbee, 2003;Stepp et al., 2004;Bouvet et al., 2007) and ob/ob mice (Schä fer et al., 2004) provide important evidence about complications of obesity, insulin resistance, hypertension, and prediabetes in the systemic microvasculature, the relative contributions of the individual components of metabolic syndrome to diabetes-associated complications cannot be dissected. Furthermore, effects of hyperglycemia and high-fat diet on the structure and mechanics of contractile medial layer are less understood. To define specific targets and develop therapeutic strategies to treat vascular complications, it is very important that the relative contributions of hyperglycemia and hyperlipidemia to vascular structure and function independent of atherosclerotic changes are well defined. The Goto-Kakizaki (GK) rat, being a spontaneous model of type 2 diabetes without the presence of comorbid complications, thus offers an excellent opportunity to study the individual role of...

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Section: Discussionmentioning

confidence: 99%

Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes

Sachidanandam

Hutchinson

Elgebaly³

et al. 2008

J Pharmacol Exp Ther

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“…Mean arterial blood pressure was recorded from weeks 14 through 18. Tail-cuff blood pressure was measured on animals not on telemetry following the same time course (Elgebaly et al, 2007). Results are given as the average of the readings during the treatment period.…”

Section: Methodsmentioning

confidence: 99%

Endothelial Endothelin B Receptor-Mediated Prevention of Cerebrovascular Remodeling Is Attenuated in Diabetes Because of Up-Regulation of Smooth Muscle Endothelin Receptors

Kelly-Cobbs¹,

Harris²,

Elgebaly³

et al. 2010

J Pharmacol Exp Ther

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Structure and function of the cerebrovasculature is critical for ischemic stroke outcome. We showed that diabetes causes cerebrovascular remodeling by activation of the endothelin A (ET A ) receptors. The goal of this study was to test the hypotheses that vasculoprotective endothelial ET B receptors are decreased and pharmacological inhibition of the ET B receptor augments vascular remodeling of middle cerebral arteries (MCAs) in type 2 diabetes. MCA structure, matrix metalloprotease (MMP) activity, and matrix proteins as well as ET A and ET B receptor profiles were assessed in control Wistar and diabetic Goto-Kakizaki rats treated with vehicle, the ET B receptor antagonist (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-[(2,6-diethylphenyl)amino]-2-oxoethyl]-2-(4-propoxyphenyl)pyrrolidine-3-carboxylic acid (A192621) (30 mg/kg/day), or the dual ET receptor antagonist bosentan (100 mg/kg/day) for 4 weeks. Diabetes increased vascular smooth muscle (VSM) ET A and ET B receptors; the increase was prevented by chronic bosentan treatment. MCA wall thickness was increased in diabetes, and this was associated with increased MMP-2 activity and collagen deposition but reduced MMP-13 activity. Because of up-regulation of VSM ET receptors in diabetes, selective ET B receptor antagonism with A192621 blunts this response, and combined ET A and ET B receptor blockade with bosentan completely prevents this response. On the other hand, A192621 treatment augmented remodeling in control animals, indicating a physiological protective role for this receptor subtype. Attenuation of changes in ET receptor profile with bosentan treatment suggests that ET-1 has a positive feedback on the expression of its receptors in the cerebrovasculature. These results emphasize that ET receptor antagonism may yield different results in healthy and diseased states.

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Section: Other Emerging Therapies For T2dmentioning

confidence: 99%

“…An experimental model in non-obese moderately diabetic rats showed that the ET-1 system contributes to increased oxidative stress [196]. ET A receptor blockade, but not ET B receptor blockade, abrogated this effect in a dose dependent manner [196]. Coronary microvascular endothelial function improved following 6 months treatment with Atrasentan, a potent and highly selective ET A receptor antagonist, in patients with coronary microvascular endothelial dysfunction on coronary angiography [197].…”

Section: Other Emerging Therapies For T2dmentioning

confidence: 99%

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

2013

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■ AbstractType 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

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Differential effects of ETA and ETB receptor antagonism on oxidative stress in type 2 diabetes

Cited by 25 publications

References 36 publications

Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes

Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes

Endothelial Endothelin B Receptor-Mediated Prevention of Cerebrovascular Remodeling Is Attenuated in Diabetes Because of Up-Regulation of Smooth Muscle Endothelin Receptors

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

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