Inhibition of Endothelin-1 Receptors Improves Impaired Nitric Oxide Synthase-Dependent Dilation of Cerebral Arterioles in Type 1 Diabetic Rats

Our goal was to test the hypothesis that administration of tetrahydrobiopterin (BH4) would improve impaired endothelial nitric oxide synthase–dependent dilation of cerebral arterioles during type 1 diabetes. In addition, we examined the influence of BH4 on levels of superoxide in brain tissue. In vivo diameter of cerebral arterioles in nondiabetic and diabetic rats was measured in response to endothelial nitric oxide synthase–dependent agonists (acetylcholine and adenosine 5′-diphosphate) and an endothelial nitric oxide synthase–independent agonist (nitroglycerine) before and during application of BH4 (1.0 µM). We also measured levels of superoxide from cortex tissue in nondiabetic and diabetic rats under basal states and during BH4. Acetylcholine and adenosine 5′-diphosphate dilated cerebral arterioles in nondiabetic rats, but this vasodilation was significantly impaired in diabetic rats. In contrast, nitroglycerine produced similar vasodilation in nondiabetic and diabetic rats. Application of BH4 did not enhance vasodilation in nondiabetic rats but improved impaired cerebral vasodilation in diabetic rats. Basal superoxide levels were increased in cortex tissue from diabetic rats, and BH4 reduced these levels to that found in nondiabetic rats. Thus, BH4 is an important mediator of endothelial nitric oxide synthase–dependent responses of cerebral arterioles in diabetes and may have therapeutic potential for the treatment of cerebral vascular disease.

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Involvement of inducible nitric oxide synthase and estrogen receptor ESR2 (ERβ) in the vascular dysfunction in female type 1 diabetic rats

Life Sciences ◽

10.1016/j.lfs.2018.11.030 ◽

2019 ◽

Vol 216 ◽

pp. 279-286 ◽

Cited By ~ 3

Author(s):

Simone Marcieli Sartoretto ◽

Fernanda Fernandes Santos ◽

Beatriz Pereira Costa ◽

Graziela Scalianti Ceravolo ◽

Rosângela Santos-Eichler ◽

...

Keyword(s):

Nitric Oxide ◽

Estrogen Receptor ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Vascular Dysfunction ◽

Diabetic Rats ◽

Female Type ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type II diabetic rats

Life Sciences ◽

10.1016/j.lfs.2003.06.029 ◽

2003 ◽

Vol 73 (26) ◽

pp. 3415-3425 ◽

Cited By ~ 26

Author(s):

RoseAnn M Schwaninger ◽

Hong Sun ◽

William G Mayhan

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Diabetic Rats ◽

Type Ii ◽

Cerebral Arterioles ◽

Oxide Synthase

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Inhibition of Rho kinase protects from ischaemia–reperfusion injury via regulation of arginase activity and nitric oxide synthase in type 1 diabetes

Diabetes and Vascular Disease Research ◽

10.1177/1479164116687935 ◽

2017 ◽

Vol 14 (3) ◽

pp. 236-245 ◽

Cited By ~ 7

Author(s):

Yahor Tratsiakovich ◽

Attila Kiss ◽

Adrian T Gonon ◽

Jiangning Yang ◽

Per-Ove Sjöquist ◽

...

Keyword(s):

Nitric Oxide ◽

Type 1 Diabetes ◽

Nitric Oxide Synthase ◽

Reperfusion Injury ◽

Diabetic Rats ◽

Arginase Activity ◽

Ischaemia Reperfusion Injury ◽

Ischaemia Reperfusion ◽

Oxide Synthase

Aim: RhoA/Rho-associated kinase and arginase are implicated in vascular complications in diabetes. This study investigated whether RhoA/Rho-associated kinase and arginase inhibition protect from myocardial ischaemia–reperfusion injury in type 1 diabetes and the mechanisms behind these effects. Methods: Rats with streptozotocin-induced type 1 diabetes and non-diabetic rats were subjected to 30 min myocardial ischaemia and 2 h reperfusion after being randomized to treatment with (1) saline, (2) RhoA/Rho-associated kinase inhibitor hydroxyfasudil, (3) nitric oxide synthase inhibitor NG-monomethyl-l-arginine monoacetate followed by hydroxyfasudil, (4) arginase inhibitor N-omega-hydroxy-nor-l-arginine, (5) NG-monomethyl-l-arginine monoacetate followed by N-omega-hydroxy-nor-l-arginine or (6) NG-monomethyl-l-arginine monoacetate given intravenous before ischaemia. Results: Myocardial arginase activity, arginase 2 expression and RhoA/Rho-associated kinase activity were increased in type 1 diabetes ( p < 0.05). RhoA/Rho-associated kinase inhibition and arginase inhibition significantly reduced infarct size in diabetic and non-diabetic rats ( p < 0.001). The cardioprotective effects of hydroxyfasudil and N-omega-hydroxy-nor-l-arginine in diabetes were abolished by nitric oxide synthase inhibition. RhoA/Rho-associated kinase inhibition attenuated myocardial arginase activity in diabetic rats via a nitric oxide synthase–dependent mechanism. Conclusion: Inhibition of either RhoA/Rho-associated kinase or arginase protects from ischaemia–reperfusion injury in rats with type 1 diabetes via a nitric oxide synthase–dependent pathway. These results suggest that inhibition of RhoA/Rho-associated kinase and arginase constitutes a potential therapeutic strategy to protect the diabetic heart against ischaemia–reperfusion injury.

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Protective Effects of Caffeic Acid Phenethyl Ester (CAPE) and Novel Cape Analogue as Inducers of Heme Oxygenase-1 in Streptozotocin-Induced Type 1 Diabetic Rats

International Journal of Molecular Sciences ◽

10.3390/ijms20102441 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2441 ◽

Cited By ~ 15

Author(s):

Valeria Sorrenti ◽

Marco Raffaele ◽

Luca Vanella ◽

Rosaria Acquaviva ◽

Loredana Salerno ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Oxidative Damage ◽

Caffeic Acid ◽

Heme Oxygenase ◽

Diabetic Rats ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Oxide Synthase

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease resulting in the destruction of insulin producing β-cells of the pancreas, with consequent insulin deficiency and excessive glucose production. Hyperglycemia results in increased levels of reactive oxygen species (ROS) and nitrogen species (RNS) with consequent oxidative/nitrosative stress and tissue damage. Oxidative damage of the pancreatic tissue may contribute to endothelial dysfunction associated with diabetes. The aim of the present study was to investigate if the potentially protective effects of phenethyl ester of caffeic acid (CAPE), a natural phenolic compound occurring in a variety of plants and derived from honeybee hive propolis, and of a novel CAPE analogue, as heme oxygenase-1 (HO-1) inducers, could reduce pancreatic oxidative damage induced by excessive amount of glucose, affecting the nitric oxide synthase/dimethylarginine dimethylaminohydrolase (NOS/DDAH) pathway in streptozotocin-induced type 1 diabetic rats. Our data demonstrated that inducible nitric oxide synthase/gamma-Glutamyl-cysteine ligase (iNOS/GGCL) and DDAH dysregulation may play a key role in high glucose mediated oxidative stress, whereas HO-1 inducers such as CAPE or its more potent derivatives may be useful in diabetes and other stress-induced pathological conditions.

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