Cerebrovascular Responses to Insulin in Rats

Katakam, Prasad V. G.; Domoki, Ferenc; Lenti, Laura; Gáspár, Tamás; Institóris, Ádám; Snipes, James A.; Busija, David W.

doi:10.1038/jcbfm.2009.177

Cited by 31 publications

(47 citation statements)

References 40 publications

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“…Consistent with our previous observations in SD rats (Katakam et al, 2009a), insulin induced vasodilation in isolated cerebral arteries of Zucker rats. However, the vasodilation to insulin was diminished in ZO compared with ZL rats signifying cerebrovascular IR.…”

Section: Cerebrovascular Insulin Resistance Accompanies Metabolic Inssupporting

confidence: 93%

“…In the present study, we identified mRNA and protein of insulin receptors in the cerebral arteries of Zucker rats comparable in size to the insulin receptors previously reported (Katakam et al, 2009a;Moloney et al, 2010).…”

Section: Discussionsupporting

confidence: 82%

“…Insulin, a metabolic hormone, has been known to exert vasodilator (Chen and Messina, 1996;Katakam et al, 2005;Oltman et al, 2000Oltman et al, , 2006 as well as vasoconstrictor (Eringa et al, 2002;Katakam et al, 2009a;Miller et al, 2002;van Veen and Chang, 1998) effects on several diverse vascular beds. Recently, we identified insulin receptors in rat cerebral arteries and have reported the cerebrovascular actions of insulin (Katakam et al, 2009b).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Katakam

Snipes

Steed

et al. 2012

J Cereb Blood Flow Metab

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Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin-induced vasodilation in ZO compared with ZL. Endothelial denudation revealed vasoconstriction to insulin that was greater in ZO compared with ZL. Nonspecific inhibition of nitric oxide synthase (NOS) paradoxically improved vasodilation in ZO. Scavenging of reactive oxygen species (ROS), supplementation of tetrahydrobiopterin (BH 4 ) precursor, and inhibition of neuronal NOS or NADPH oxidase or cyclooxygenase (COX) improved insulin-induced vasodilation in ZO. Immunoblot experiments revealed that insulin-induced phosphorylation of Akt, endothelial NOS, and expression of GTP cyclohydrolase-I (GTP-CH) were diminished, but phosphorylation of PKC and ERK was enhanced in ZO arteries. Fluorescence studies showed increased ROS in ZO arteries in response to insulin that was sensitive to NOS inhibition and BH 4 supplementation. Thus, a vicious cycle of abnormal insulin-induced ROS generation instigating NOS uncoupling leading to further ROS production underlies the cerebrovascular IR in ZO rats. In addition, decreased bioavailability and impaired synthesis of BH 4 by GTP-CH induced by insulin promoted NOS uncoupling.

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Section: Cerebrovascular Insulin Resistance Accompanies Metabolic Inssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Katakam

Snipes

Steed

et al. 2012

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

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“…Insulin increases cortical blood flow in rats at doses of 120 ng/mL in superfused cerebral spinal fluid (40). We may induce similar insulin levels in cerebral vessels.…”

Section: Discussionmentioning

confidence: 89%

Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An ¹⁸F-FDG PET Study

et al. 2013

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We addressed the questions of how cerebral glucose transport and phosphorylation change under acute hypoglycemia and what the underlying mechanisms of adaptation are. Methods: Quantitative 18 F-FDG PET combined with the acquisition of real-time arterial input function was performed on mice. Hypoglycemia was induced and maintained by insulin infusion. PET data were analyzed with the 2-tissue-compartment model for 18 F-FDG, and the results were evaluated with Michaelis-Menten saturation kinetics. Results: Glucose clearance from plasma to brain (K 1,glc ) and the phosphorylation rate constant increased with decreasing plasma glucose (G p ), in particular at a G p of less than 2.5 mmol/L. Estimated cerebral glucose extraction ratios taking into account an increased cerebral blood flow (CBF) at a G p of less than 2 mmol/L were between 0.14 and 0.79. CBF-normalized K 1,glc values were in agreement with saturation kinetics. Phosphorylation rate constants indicated intracellular glucose depletion at a G p of less than 2-3 mmol/L. When brain regions were compared, glucose transport under hypoglycemia was lowest in the hypothalamus. Conclusion: Alterations in glucose transport and phosphorylation, as well as intracellular glucose depletion, under acute hypoglycemia can be modeled by saturation kinetics taking into account an increase in CBF. Distinct transport kinetics in the hypothalamus may be involved in its glucose-sensing function.

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“…Fluo-4 AM was used to determine [Ca 2ϩ ]i (20). Diaminorhodamine-4M (DAR-4M) was used to determine NO (18,22). All fluoroprobes were obtained from Molecular Probes (Eugene, OR).…”

Section: Methodsmentioning

confidence: 99%

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Katakam

Dutta

Sure

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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-The diverse signaling events following mitochondrial depolarization in neurons are not clear. We examined for the first time the effects of mitochondrial depolarization on mitochondrial function, intracellular calcium, neuronal nitric oxide synthase (nNOS) activation, and nitric oxide (NO) production in cultured neurons and perivascular nerves. Cultured rat primary cortical neurons were studied on 7-10 days in vitro, and endothelium-denuded cerebral arteries of adult Sprague-Dawley rats were studied ex vivo. Diazoxide and BMS-191095 (BMS), activators of mitochondrial K ATP channels, depolarized mitochondria in cultured neurons and increased cytosolic calcium levels. However, the mitochondrial oxygen consumption rate was unaffected by mitochondrial depolarization. In addition, diazoxide and BMS not only increased the nNOS phosphorylation at positive regulatory serine 1417 but also decreased nNOS phosphorylation at negative regulatory serine 847. Furthermore, diazoxide and BMS increased NO production in cultured neurons measured with both fluorescence microscopy and electron spin resonance spectroscopy, which was sensitive to inhibition by the selective nNOS inhibitor 7-nitroindazole (7-NI). Diazoxide also protected cultured neurons against oxygen-glucose deprivation, which was blocked by NOS inhibition and rescued by NO donors. Finally, BMS induced vasodilation of endothelium denuded, freshly isolated cerebral arteries that was diminished by 7-NI and tetrodotoxin. Thus pharmacological depolarization of mitochondria promotes activation of nNOS leading to generation of NO in cultured neurons and endothelium-denuded arteries. Mitochondrial-induced NO production leads to increased cellular resistance to lethal stress by cultured neurons and to vasodilation of denuded cerebral arteries. MITOCHONDRIAL MEMBRANE POTENTIAL is a critical regulator of cellular activity and survival and is controlled by a variety of factors including the ATP-sensitive potassium (mitoK ATP ) channels located on the inner mitochondrial membrane (2). Pharmacological activators of mitoK ATP channels, such as BMS-191095 (BMS) and diazoxide, decrease the mitochondrial membrane potential by facilitating the influx of potassium from cytosol into the matrix (2). Signaling events following mitochondrial depolarization appear to be diverse in the various cell types comprising the neurovascular unit (cerebral vascular endothelium and smooth muscle, perivascular neurons, parenchymal neurons, and glia). Both BMS and diazoxide applications result in dilation of isolated cerebral arteries; however, individual effects on vascular smooth muscle and endothelium, which contribute to the overall vascular effect, are completely different (20,22,35,42). Thus BMS and diazoxide relax cerebral vascular smooth muscle cells via generation of localized calcium sparks by sarcoplasmic reticulum linked to mitochondrial depolarization, resulting in decreased global intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (20, 42). Conversely, mitochondrial depolarization in cerebral endothe...

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Cerebrovascular Responses to Insulin in Rats

Cited by 31 publications

References 40 publications

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An ¹⁸F-FDG PET Study

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

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Cerebrovascular Responses to Insulin in Rats

Cited by 31 publications

References 40 publications

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An 18F-FDG PET Study

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

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Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An ¹⁸F-FDG PET Study