Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat

2009 ◽  
Vol 296 (5) ◽  
pp. H1388-H1397 ◽  
Author(s):  
Takayuki Matsumoto ◽  
Keiko Ishida ◽  
Naoaki Nakayama ◽  
Tsuneo Kobayashi ◽  
Katsuo Kamata
Keyword(s):  
Mesenteric Artery ◽  
Wistar Rats ◽  
Molecular Mechanisms ◽  
Mesenteric Arteries ◽  
No Production ◽  
Erk Pathway ◽  
Gk Rats ◽  
Protein Expressions ◽  
Type 2 Diabetic

Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. However, no abnormalities in the vascular responsiveness to ET-1 have been identified in the chronic stage of type 2 diabetes. Our goal was to look for abnormalities in the roles played by ET receptors (ETA and ETB) in the mesenteric artery of the type 2 diabetic Goto-Kakizaki (GK) rat and to identify the molecular mechanisms involved. Using mesenteric arteries from later-stage (32–38 wk old) individuals, we compared the ET-1-induced contraction and the relaxation induced by the selective ETB receptor agonist IRL1620 between GK rats and control Wistar rats. Mesenteric artery ERK activity and the protein expressions for ET receptors and MEK were also measured. In GK rats (vs. age-matched Wistar rats), we found as follows. 1) The ET-1-induced contraction was greater and was attenuated by BQ-123 (ETA antagonist) but not by BQ-788 (ETB antagonist). In the controls, BQ-788 augmented this contraction. 2) Both the relaxation and nitric oxide (NO) production induced by IRL1620 were reduced. 3) ET-1-induced contraction was enhanced by NG-nitro-l-arginine (l-NNA; NO synthase inhibitor) but suppressed by sodium nitroprusside (NO donor). 4) The enhanced ET-1-induced contraction was reduced by MEK/ERK pathway inhibitors (PD-98059 or U0126). 5) ET-1-stimulated ERK activation was increased, as were the ETA and MEK1/2 protein expressions. 6) Mesenteric ET-1 content was increased. These results suggest that upregulation of ETA, a defect in ETB-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism mediating the hyperreactivity to ET-1 examined in this study.

Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats

2011 ◽  
Vol 300 (4) ◽  
pp. H1174-H1181 ◽  
Author(s):  
Julia Grönros ◽  
Christian Jung ◽  
Jon O. Lundberg ◽  
Ruha Cerrato ◽  
Claes-Göran Östenson ◽  
...  
Keyword(s):  
Vascular Function ◽  
Wistar Rats ◽  
Diabetic Rats ◽  
Microvascular Function ◽  
Vascular Integrity ◽  
Gk Rats ◽  
Type 2 Diabetic ◽  
Coronary Microvascular Function

Nitric oxide (NO) is crucial for maintaining normal endothelial function and vascular integrity. Increased arginase activity in diabetes might compete with NO synthase (NOS) for their common substrate arginine, resulting in diminished production of NO. The aim of this study was to evaluate coronary microvascular function in type 2 diabetic Goto-Kakizaki (GK) rats using in vivo coronary flow velocity reserve (CFVR) and the effect of arginase inhibition to restore vascular function. Different groups of GK and Wistar rats were given vehicle, the arginase inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA), l-arginine, and the NOS inhibitor NG-monomethyl -l-arginine (l-NMMA). GK rats had impaired CFVR compared with Wistar rats (1.31 ± 0.09 vs. 1.87 ± 0.05, P < 0.001). CFVR was restored by nor-NOHA treatment compared with vehicle in GK rats (1.71 ± 0.13 vs. 1.23 ± 0.12, P < 0.05) but remained unchanged in Wistar rats (1.88 ± 0.10 vs. 1.79 ± 0.16). The beneficial effect of nor-NOHA in GK rats was abolished after NOS inhibition. CFVR was not affected by arginine compared with vehicle. Arginase II expression was increased in the aorta and myocardium from GK rats compared with Wistar rats. Citrulline-to-ornithine and citrulline-to-arginine ratios measured in plasma increased significantly more in GK rats than in Wistar rats after nor-NOHA treatment, suggesting a shift of arginine utilization from arginase to NOS. In conclusion, coronary artery microvascular function is impaired in the type 2 diabetic GK rat. Treatment with nor-NOHA restores the microvascular function by a mechanism related to increased utilization of arginine by NOS and increased NO availability.

scholarly journals Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats

Pharmacology ◽  
2021 ◽  
pp. 1-7
Author(s):  
Ali Mahdi ◽  
Tong Jiao ◽  
Yahor Tratsiakovich ◽  
Bernhard Wernly ◽  
Jiangning Yang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Wistar Rats ◽  
Microvascular Complications ◽  
Mesenteric Arteries ◽  
Tyrosine Kinase Receptor ◽  
Gk Rats ◽  
Glucose Levels ◽  
Arterial Blood

<b><i>Introduction:</i></b> Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. <b><i>Methods:</i></b> Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. <b><i>Results:</i></b> Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. <b><i>Conclusions:</i></b> This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

2009 ◽  
Vol 296 (3) ◽  
pp. H719-H727 ◽  
Author(s):  
Aliaksandr A. Bulhak ◽  
Christian Jung ◽  
Claes-Göran Östenson ◽  
Jon O. Lundberg ◽  
Per-Ove Sjöquist ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
No Synthase ◽  
Ischemic Myocardium ◽  
No Production ◽  
Gk Rats ◽  
Nitrite Nitrate ◽  
Type 2 Diabetic

Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferator-activated receptor-α (PPAR-α) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR-α would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and age-matched Wistar rats (n ≥ 7) were given either 1) the PPAR-α agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor NG-nitro-l-arginine (l-NNA), 4) l-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/nitrate were determined. The IS was 75 ± 3% and 72 ± 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 ± 3% in Wistar ( P < 0.05) and to 46 ± 5% in GK rats ( P < 0.001). The addition of either l-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 ± 5% and 65 ± 5%, respectively) and GK (IS, 66 ± 4% and 64 ± 4%, P < 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats ( P < 0.05). The results suggest that PPAR-α activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.

scholarly journals Adrenoceptor Expression and Diurnal Rhythms of Melatonin and Its Precursors in the Pineal Gland of Type 2 Diabetic Goto-Kakizaki Rats

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2483-2493 ◽  
Author(s):  
Andreas Gunter Bach ◽  
Eckhard Mühlbauer ◽  
Elmar Peschke
Keyword(s):  
Pineal Gland ◽  
Wistar Rats ◽  
Protective Role ◽  
Diurnal Rhythms ◽  
Diabetic Rat ◽  
Gk Rats ◽  
Melatonin Synthesis ◽  
First Time ◽  
Type 2 Diabetic

A decrease in the nighttime release of the pineal hormone melatonin is associated with aging and chronic diseases in animals an humans. Melatonin has a protective role in type 2 diabetes; however, its synthesis itself is affected in the disease. The aim of this study was to detect crucially impaired steps in the pineal melatonin synthesis of type 2 diabetic Goto-Kakizaki (GK) rats. Therefore, plasma melatonin concentrations and the pineal content of melatonin and its precursors (tryptophan, 5-hydroxytryptophan, serotonin, and N-acetylserotonin) were quantified in GK rats compared with Wistar rats (each group 8 and 50 wk old) in a diurnal manner (four animals per group and per time point). Additionally, the expression of pineal adrenoceptor subtype mRNA was investigated. We found that in diabetic GK rats, 1) inhibitory α-2-adrenoceptors are significantly more strongly expressed than in Wistar rats, 2) the formation of 5-hydroxytryptophan is crucially impaired, and 3) the pineal gland protein content is significantly reduced compared with that in Wistar rats. This is the first time that melatonin synthesis is examined in a type 2 diabetic rat model in a diurnal manner. The present data unveil several reasons for a reduced melatonin secretion in diabetic animals and present an important link in the interaction between melatonin and insulin.

Relationship between PDK1 and contraction in carotid arteries in Goto-Kakizaki rat, a spontaneous type 2 diabetic animal model

2017 ◽  
Vol 95 (4) ◽  
pp. 459-462 ◽  
Author(s):  
Shun Watanabe ◽  
Takayuki Matsumoto ◽  
Kumiko Taguchi ◽  
Tsuneo Kobayashi
Keyword(s):  
Wistar Rats ◽  
Carotid Arteries ◽  
Diabetic Animal ◽  
Nitric Oxide Synthase Inhibitor ◽  
Gk Rats ◽  
Dependent Protein ◽  
The Difference ◽  
Synthase Inhibitor ◽  
Type 2 Diabetic

We studied the relationship between 3-phosphoinositide-dependent protein kinase 1 (PDK1) and contractions induced by serotonin, phenylephrine, and thromboxane A2 mimetic (U46619) in the presence of nitric oxide synthase inhibitor in the carotid arteries of Goto-Kakizaki (GK) rats, a spontaneous type 2 diabetic model, in the chronic stage of disease. Serotonin-induced contraction was greater in the GK rats than in the control Wistar rats. A specific PDK1 inhibitor (GSK2334470) decreased the serotonin-induced contraction in the GK rats but not in the Wistar rats, and the difference in such contraction was abolished with this treatment. In GK rats, phenylephrine-induced contraction exhibited a leftward shift and U46619-induced contraction was greater still. Phenylephrine- and U46619-induced contractions were reduced by GSK2334470 in both groups. These results suggest, for the first time, that the contribution of PDK1 is different among 3 vasoconstrictors and that PDK1 contributed to increased serotonin-induced contraction in the carotid arteries of GK rats.

scholarly journals Transcriptomic responses of hypothalamus to acute exercise in type 2 diabetic Goto-Kakizaki rats

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7743 ◽  
Author(s):  
Shuying Fu ◽  
Yuhuan Meng ◽  
Shudai Lin ◽  
Wenlu Zhang ◽  
Yuting He ◽  
...  
Keyword(s):  
Nervous System ◽  
Lipid Metabolism ◽  
Wistar Rats ◽  
Energy Homeostasis ◽  
Acute Exercise ◽  
Genome Database ◽  
Gk Rats ◽  
Prevention And Treatment ◽  
Type 2 Diabetic

The hypothalamus has an integral role in energy homeostasis regulation, and its dysfunctions lead to the development of type 2 diabetes (T2D). Physical activity positively affects the prevention and treatment of T2D. However, there is not much information on the adaptive mechanisms of the hypothalamus. In this study, RNA sequencing was used to determine how acute exercise affects hypothalamic transcriptome from both type 2 diabetic Goto-Kakizaki (GK) and control Wistar rats with or without a single session of running (15 m/min for 60 min). Through pairwise comparisons, we identified 957 differentially expressed genes (DEGs), of which 726, 197, and 98 genes were found between GK and Wistar, exercised GK and GK, and exercised Wistar and Wistar, respectively. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment revealed that lipid metabolism-related terms and pathways were enriched in GK and exercised GK rats, and nervous system related terms and pathways were enriched in exercised GK and Wistar rats. Furthermore, 45 DEGs were associated with T2D and related phenotypes according to the annotations in the Rat Genome Database. Among these 45 DEGs, several genes (Plin2, Cd36, Lpl, Wfs1, Cck) related to lipid metabolism or the nervous system are associated with the exercise-induced benefits in the hypothalamus of GK rats. Our findings might assist in identifying potential therapeutic targets for T2D prevention and treatment.

scholarly journals Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction

2018 ◽  
Vol 19 (12) ◽  
pp. 3942 ◽  
Author(s):  
Ali Mahdi ◽  
Tong Jiao ◽  
Yahor Tratsiakovich ◽  
Jiangning Yang ◽  
Claes-Göran Östenson ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Mesenteric Arteries ◽  
Vascular Contraction ◽  
Gk Rats ◽  
Vasoconstrictor Response

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.

scholarly journals Altered Glucose and Insulin Responses to Brain Medullary Thyrotropin-Releasing Hormone (TRH)-Induced Autonomic Activation in Type 2 Diabetic Goto-Kakizaki Rats

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5425-5432 ◽  
Author(s):  
Yan Ao ◽  
Natalie Toy ◽  
Moon K. Song ◽  
Vay Liang W. Go ◽  
Hong Yang
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Wistar Rats ◽  
Mrna Levels ◽  
Gk Rats ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Autonomic Activation ◽  
Insulin Responses

Insulin secretion is impaired in type 2 diabetes (T2D). The insulin and glucose responses to central autonomic activation induced by excitation of brain medullary TRH receptors were studied in T2D Goto-Kakizaki (GK) rats. Blood glucose levels in normally fed, pentobarbital-anesthetized GK and nondiabetic Wistar rats were 193 and 119 mg/100 ml in males and 214 and 131 mg/100 ml in females. Intracisternal injection (ic) of the stable TRH analog RX 77368 (10 ng) induced significantly higher insulin response in both genders of overnight-fasted GK rats compared with Wistar rats and slightly increased blood glucose in female Wistar rats but significantly decreased it from 193 to 145 mg/100 ml in female GK rats. RX 77368 (50 ng) ic induced markedly greater glucose and relatively weaker insulin responses in male GK rats than Wistar rats. Bilateral vagotomy blocked ic RX 77368-induced insulin secretion, whereas adrenalectomy abolished its hyperglycemic effect. In adrenalectomized male GK but not Wistar rats, ic RX 77368 (50 ng) dramatically increased serum insulin levels by 6.5-fold and decreased blood glucose levels from 154 to 98 mg/100 ml; these changes were prevented by vagotomy. GK rats had higher basal pancreatic insulin II mRNA levels but a lower response to ic RX 77368 (50 ng) compared with Wistar rats. These results indicate that central-vagal activation-induced insulin secretion is susceptible in T2D GK rats. However, the dominant sympathetic-adrenal response to medullary TRH plays a suppressing role on vagal-mediated insulin secretion. This unbalanced vago-sympathetic activation by medullary TRH may contribute to the impaired insulin secretion in T2D.

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