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

2017 ◽  
Vol 14 (3) ◽  
pp. 236-245 ◽  
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.

Timing of Administration of Dexamethasone or the Nitric Oxide Synthase Inhibitor, Nitro-l-Arginine Methyl Ester, is Critical for Effective Treatment of Ischaemia-Reperfusion Injury to Rat Skeletal Muscle

1997 ◽  
Vol 93 (2) ◽  
pp. 167-174 ◽  
Author(s):  
Baimeng Zhang ◽  
Kenneth R. Knight ◽  
Bruce Dowsing ◽  
Elizabeth Guida ◽  
Long H. Phan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Methyl Ester ◽  
Nitric Oxide Synthase ◽  
Reperfusion Injury ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Nos Inhibitors ◽  
Oxide Synthase ◽  
Inducible Nos

1. The effects of the nitric oxide synthase (NOS) inhibitors, NG-nitro-l-arginine-methyl ester (l-NAME), nitroiminoethyl-l-ornithine and S-methylisothiourea on skeletal muscle survival following 2 h of tourniquet ischaemia and 24 h of reperfusion were compared with those of the antiinflammatory steroid, dexamethasone. 2. Administration of each of the NOS inhibitors or dexamethasone 30 min before reperfusion reduced the degree of skeletal muscle necrosis 24 h after reperfusion. 3. The influence of timing of drug administration was investigated. l-NAME administered 30 min before reperfusion, at 3 h after reperfusion, but not thereafter, significantly improved muscle survival compared with saline-treated controls. Dexamethasone administered 30 min before, or at 3 or 8 h after reperfusion, but not at 16 h, significantly improved muscle survival, but neither agent had protective effects when administered before ischaemia. 4. After 8 h of reperfusion of ischaemic skeletal muscle, cell-free homogenates contained Ca2+-independent (inducible) NOS activity which was reduced in dexamethasone-treated (2.5 mg/kg) rats. Furthermore, inducible NOS mRNA levels, as detected by reverse transcriptase-PCR, were increased after 8 h of reperfusion in saline, but not in dexamethasone-treated rats. 5. These data suggest a significant deleterious effect of endogenous NO which may be restricted to the first 3 h of the reperfusion phase of ischaemia-reperfusion injury, and raise the possibility of effective treatment of incipient reperfusion injury, even after several hours of reperfusion.

Targeted disruption of the nitric oxide synthase 2 gene protects against ischaemia/reperfusion injury to skeletal muscle

2001 ◽  
Vol 194 (1) ◽  
pp. 109-115 ◽  
Author(s):  
Jane E. Barker ◽  
Kenneth R. Knight ◽  
Rosalind Romeo ◽  
John V. Hurley ◽  
Wayne A. Morrison ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Nitric Oxide Synthase ◽  
Reperfusion Injury ◽  
Targeted Disruption ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

scholarly journals Tetrahydrobiopterin rescues impaired responses of cerebral resistance arterioles during type 1 diabetes

2016 ◽  
Vol 14 (1) ◽  
pp. 33-39 ◽  
Author(s):  
William G Mayhan ◽  
Denise M Arrick
Keyword(s):  
Nitric Oxide ◽  
Type 1 Diabetes ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Therapeutic Potential ◽  
Diabetic Rats ◽  
Cerebral Arterioles ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

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.

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

Life Sciences ◽  
2019 ◽  
Vol 216 ◽  
pp. 279-286 ◽  
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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