Publications by authors named "William G Mayhan"

60 Publications

Rosiglitazone restores nitric oxide synthase-dependent reactivity of cerebral arterioles in rats exposed to prenatal alcohol.

Alcohol Clin Exp Res 2021 Jul 12;45(7):1359-1369. Epub 2021 Jun 12.

Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.

Background: Prenatal exposure to alcohol leads to a greater incidence of many cardiovascular-related diseases, presumably via a mechanism that may involve increased oxidative stress. An agonist of peroxisome proliferator-activated receptor gamma (PPARγ; rosiglitazone) has been shown to suppress alcohol-induced neuroinflammation and oxidative stress. The goal of this study was to determine whether acute and chronic treatment with rosiglitazone could restore or prevent impaired nitric oxide synthase (NOS)-dependent responses of cerebral arterioles in male and female adult (14-16 weeks old) rats exposed to alcohol in utero.

Methods: We fed Sprague-Dawley dams a liquid diet with or without 3% ethanol for the duration of their pregnancy (21-23 days). In the first series of studies, we examined the reactivity of cerebral arterioles to eNOS- (ADP), nNOS-dependent (NMDA), and NOS-independent agonists in male and female adult rats before and during acute (1 hour) topical application of rosiglitazone (1 µM). In a second series of studies, we examined the influence of chronic treatment with rosiglitazone (3 mg/kg/day in drinking water for 2-3 weeks) on the responses of cerebral arterioles in male and female adult rats exposed to alcohol in utero.

Results: We found that in utero exposure to alcohol similarly reduced responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in male and female adult rats. In addition, acute treatment of the male and female adult rats with rosiglitazone similarly restored this impairment in cerebral vascular function to that observed in controls. We also found that chronic treatment with rosiglitazone prevented impaired vascular function in male and female adult rats that were exposed to alcohol in utero.

Conclusions: PPARγ activation may be an effective and relevant treatment to reverse or prevent cerebral vascular abnormalities associated with prenatal exposure to alcohol.
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http://dx.doi.org/10.1111/acer.14634DOI Listing
July 2021

A cannabinoid type 2 (CB2) receptor agonist augments NOS-dependent responses of cerebral arterioles during type 1 diabetes.

Microvasc Res 2021 01 24;133:104077. Epub 2020 Sep 24.

Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD 57069, United States of America. Electronic address:

While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease state such as type 1 diabetes (T1D). Our goal was to test the hypothesis that administration of a CB2 agonist (JWH-133) would improve impaired endothelial (eNOS)- and neuronal (nNOS)-dependent dilation of cerebral arterioles during T1D. In vivo diameter of cerebral arterioles in nondiabetic and T1D rats was measured in response to an eNOS-dependent agonist (adenosine 5'-diphosphate; ADP), an nNOS-dependent agonist (N-methyl-d-aspartate; NMDA), and an NOS-independent agonist (nitroglycerin) before and 1 h following JWH-133 (1 mg/kg IP). Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in T1D rats. Treatment with JWH-133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and T1D rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and T1D rats, and JWH-133 did not influence responses to nitroglycerin in either group. The restoration in responses to the agonists by JWH-133 could be inhibited by treatment with a specific inhibitor of CB2 receptors (AM-630; 3 mg/kg IP). Thus, activation of CB2 receptors can potentiate reactivity of cerebral arterioles during physiologic and pathophysiologic states. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular diseases via a mechanism that can increase cerebral blood flow.
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http://dx.doi.org/10.1016/j.mvr.2020.104077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704564PMC
January 2021

Author Correction: Effect of Low-Dose Alcohol Consumption on Inflammation Following Transient Focal Cerebral Ischemia in Rats.

Sci Rep 2019 Apr 17;9(1):6404. Epub 2019 Apr 17.

Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-42589-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470153PMC
April 2019

Dose-Dependent Influences of Ethanol on Ischemic Stroke: Role of Inflammation.

Front Cell Neurosci 2019 12;13. Epub 2019 Feb 12.

Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States.

Chronic ethanol consumption dose-dependently affects both incidence and prognosis of ischemic stroke. Our goal was to determine whether the influence of chronic ethanol consumption on ischemic stroke is related to an altered inflammatory profile in the brain. Male C57BL/6J mice were divided into six groups and gavage fed with 0.175, 0.35, 0.7, 1.4, 2.8 g/kg/day ethanol or volume-matched water once a day for 8 weeks. Adhesion molecules, microglial activation, neutrophil infiltration, pro- and anti-inflammatory cytokines/chemokines, blood-brain barrier (BBB) permeability, and matrix metallopeptidases (MMPs) in the cerebral cortex before and following a 90-min unilateral middle cerebral artery occlusion (MCAO)/24-h reperfusion were evaluated. Brain ischemia/reperfusion (I/R) injury was significantly reduced in 0.7 g/kg/day ethanol group (peak blood ethanol concentration: 9 mM) and worsened in 2.8 g/kg/day ethanol group (peak blood ethanol concentration: 37 mM). Baseline E-selectin was downregulated in all ethanol groups, whereas baseline intercellular adhesion molecule-1 (ICAM-1) was only downregulated in 0.35 and 0.7 g/kg/day ethanol groups. Interestingly, baseline vascular cell adhesion molecule-1 (VCAM-1) was upregulated in 0.35, 0.7, and 1.4 g/kg/day ethanol groups. Post-ischemic upregulation of ICAM-1 and E-selectin were suppressed in all ethanol groups. Post-ischemic neutrophil infiltration and microglial activation were significantly less in the low-moderate (0.175-1.4 g/kg/day) ethanol groups but greater in the 2.8 g/kg/day ethanol group compared to the vehicle group. At basal conditions, ethanol increased one pro- and two anti-inflammatory cytokines/chemokines at the 0.7 g/kg/day dose, and 13 pro- and eight anti-inflammatory cytokines/chemokines at the 2.8 g/kg/day dose. After ischemia, 0.7 g/kg/day ethanol suppressed post-ischemic pro-inflammatory cytokines/chemokines and enhanced post-ischemic anti-inflammatory cytokines/chemokines. Moreover, 0.7 g/kg/day ethanol significantly reduced baseline MMP-9 activity and alleviated post-ischemic BBB breakdown. On the other hand, 2.8 g/kg/day ethanol worsened post-ischemic BBB breakdown. Our findings suggest that low-moderate ethanol consumption may prevent ischemic stroke and reduce brain I/R injury by suppressing inflammation, whereas heavy alcohol consumption may induce ischemic stroke and worsen brain I/R injury by aggravating inflammation.
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http://dx.doi.org/10.3389/fncel.2019.00006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396710PMC
February 2019

In Utero Exposure to Alcohol Impairs Reactivity of Cerebral Arterioles and Increases Susceptibility of the Brain to Damage Following Ischemia/Reperfusion in Adulthood.

Alcohol Clin Exp Res 2019 04 7;43(4):607-616. Epub 2019 Mar 7.

Division of Basic Biomedical Sciences , Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota.

Background: Maternal consumption of alcohol produces abnormalities in the developing fetus and can contribute to an increased incidence of many cardiovascular-related diseases. The first goal of this study was to determine whether in utero exposure to alcohol influences reactivity of cerebral arterioles in adult (12 to 15 weeks old) rats. The second goal of this study was to examine whether in utero exposure to alcohol increased the susceptibility of the brain to damage following an ischemic event in adult rats.

Methods: We fed Sprague Dawley dams a liquid diet with or without alcohol (3% ethanol) for the duration of their pregnancy (21 to 23 days). In the first series of studies, we examined reactivity of cerebral arterioles to endothelial nitric oxide synthase (eNOS)- (adenosine diphosphate [ADP]) and neuronal nitric oxide synthase (nNOS)-dependent N-methyl-D-aspartate (NMDA, and NOS-independent agonists in adult rats before and during application of l-NMMA. In another series of studies, we examined infarct volume following middle cerebral artery occlusion in adult offspring exposed to alcohol in utero. In both series of studies, we also determined the role for an increase in oxidative stress by feeding dams apocynin for the duration of their pregnancy.

Results: We found that in utero exposure to alcohol reduced responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in adult rats. In addition, treatment of the dams with apocynin prevented this impairment in cerebral vascular function. We also found that in utero exposure to alcohol worsened brain damage following ischemia/reperfusion in adult rats and that treatment of dams with apocynin prevented this increase in brain damage following ischemia/reperfusion.

Conclusions: We suggest that our findings may have important implications for the pathogenesis of brain abnormalities associated with fetal alcohol exposure.
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http://dx.doi.org/10.1111/acer.13979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538292PMC
April 2019

Mito-Tempo prevents nicotine-induced exacerbation of ischemic brain damage.

J Appl Physiol (1985) 2018 07 8;125(1):49-57. Epub 2018 Feb 8.

Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, South Dakota.

Nicotine may contribute to the pathogenesis of cerebrovascular disease via the generation of reactive oxygen species (ROS). Overproduction of ROS leads to brain damage by intensifying postischemic inflammation. Our goal was to determine the effect of Mito-Tempo, a mitochondria-targeted antioxidant, on ischemic brain damage and postischemic inflammation during chronic exposure to nicotine. Male Sprague-Dawley rats were divided into four groups: control, nicotine, Mito-Tempo-treated control, and Mito-Tempo-treated nicotine. Nicotine (2 mg·kg·day) was administered via an osmotic minipump for 4 wk. Mito-Tempo (0.7 mg·kg·day ip) was given for 7 days before cerebral ischemia. Transient focal cerebral ischemia was induced by occlusion of the middle cerebral artery for 2 h. Brain damage and inflammation were evaluated after 24 h of reperfusion by measuring infarct volume, expression of adhesion molecules, activity of matrix metalloproteinase, brain edema, microglial activation, and neutrophil infiltration. Nicotine exacerbated infarct volume and worsened neurological deficits. Nicotine did not alter baseline ICAM-1 expression, matrix metallopeptidase-2 activity, microglia activation, or neutrophil infiltration but increased these parameters after cerebral ischemia. Mito-Tempo did not have an effect in control rats but prevented the chronic nicotine-induced augmentation of ischemic brain damage and postischemic inflammation. We suggest that nicotine increases brain damage following cerebral ischemia via an increase in mitochondrial oxidative stress, which, in turn, contributes to postischemic inflammation. NEW & NOTEWORTHY Our findings have important implications for the understanding of mechanisms contributing to increased susceptibility of the brain to damage in smokers and users of nicotine-containing tobacco products.
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http://dx.doi.org/10.1152/japplphysiol.01084.2017DOI Listing
July 2018

Effect of Low-Dose Alcohol Consumption on Inflammation Following Transient Focal Cerebral Ischemia in Rats.

Sci Rep 2017 10 2;7(1):12547. Epub 2017 Oct 2.

Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.

Increasing evidence suggest that low-dose alcohol consumption (LAC) reduces the incidence and improves the functional outcome of ischemic stroke. We determined the influence of LAC on post-ischemic inflammation. Male Sprague-Dawley rats were divided into 3 groups, an ethanol (13.5% alcohol) group, a red wine (Castle Rock Pinot Noir, 13.5% alcohol) group, and a control group. The amount of alcohol given to red wine and ethanol groups was 1.4 g/kg/day. After 8 weeks, the animals were subjected to a 2-hour middle cerebral artery occlusion (MCAO) and sacrificed at 24 hours of reperfusion. Cerebral ischemia/reperfusion (I/R) injury, expression of adhesion molecules and pro- and anti-inflammatory cytokines/chemokines, microglial activation and neutrophil infiltration were evaluated. The total infarct volume and neurological deficits were significantly reduced in red wine- and ethanol-fed rats compared to control rats. Both red wine and ethanol suppressed post-ischemic expression of adhesion molecules and microglial activation. In addition, both red wine and ethanol upregulated expression of tissue inhibitor of metalloproteinases 1 (TIMP-1), downregulated expression of proinflammatory cytokines/chemokines, and significantly alleviated post-ischemic expression of inflammatory mediators. Furthermore, red wine significantly reduced post-ischemic neutrophil infiltration. Our findings suggest that LAC may protect the brain against its I/R injury by suppressing post-ischemic inflammation.
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http://dx.doi.org/10.1038/s41598-017-12720-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624984PMC
October 2017

In utero exposure to alcohol alters reactivity of cerebral arterioles.

J Cereb Blood Flow Metab 2019 02 25;39(2):332-341. Epub 2017 Aug 25.

2 Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.

Our goal was to examine whether in utero exposure to alcohol impaired reactivity of cerebral arterioles during development. We fed Sprague-Dawley dams a liquid diet with or without alcohol (3% ethanol) for the duration of pregnancy (21-23 days). Around 4-6 weeks after birth, we examined reactivity of cerebral arterioles to eNOS- (ADP) and nNOS-dependent (NMDA) agonists in the offspring. We found that in utero exposure to alcohol attenuated responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in rats exposed to alcohol in utero. L-NMMA reduced responses to agonists in control rats, but not in rats exposed to alcohol in utero. Treatment of dams with apocynin for the duration of pregnancy rescued the impairment in reactivity to ADP and NMDA in the offspring. Protein expression of NOX-2 and NOX-4 was increased in alcohol rats compared to control rats. We also found an increase in superoxide levels in the cortex of rats exposed to alcohol in utero. Our findings suggest that in utero exposure to alcohol impairs eNOS and nNOS reactivity of cerebral arterioles via a chronic increase in oxidative stress.
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http://dx.doi.org/10.1177/0271678X17728163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365603PMC
February 2019

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

Diab Vasc Dis Res 2017 01 14;14(1):33-39. Epub 2016 Nov 14.

Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.

Our goal was to test the hypothesis that administration of tetrahydrobiopterin (BH) would improve impaired endothelial nitric oxide synthase-dependent dilation of cerebral arterioles during type 1 diabetes. In addition, we examined the influence of BH 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 BH (1.0 µM). We also measured levels of superoxide from cortex tissue in nondiabetic and diabetic rats under basal states and during BH 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 BH 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 BH reduced these levels to that found in nondiabetic rats. Thus, BH 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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http://dx.doi.org/10.1177/1479164116675490DOI Listing
January 2017

Severe respiratory changes at end stage in a FUS-induced disease state in adult rats.

BMC Neurosci 2016 10 28;17(1):69. Epub 2016 Oct 28.

Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.

Background: Fused in sarcoma (FUS) is an RNA-binding protein associated with the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. ALS manifests in patients as a progressive paralysis which leads to respiratory dysfunction and failure, the primary cause of death in ALS. We expressed human FUS in rats to determine if FUS would induce ALS relevant respiratory changes to serve as an early stage disease indicator. The FUS expression was initiated in adult rats by way of an intravenously administered adeno-associated virus vector serotype 9 (AAV9) providing an adult onset model.

Results: The rats developed progressive motor impairments observed as early as 2-3 weeks post gene transfer. Respiratory abnormalities manifested 4-7 weeks post gene transfer including increased respiratory frequency and decreased tidal volume. Rats with breathing abnormalities also had arterial blood acidosis. Similar detailed plethysmographic changes were found in adult rats injected with AAV9 TDP-43. FUS gene transfer to adult rats yielded a consistent pre-clinical model with relevant motor paralysis in the early to middle stages and respiratory dysfunction at the end stage. Both FUS and TDP-43 yielded a similar consistent disease state.

Conclusions: This modeling method yields disease relevant motor and respiratory changes in adult rats. The reproducibility of the data supports the use of this method to study other disease related genes and their combinations as well as a platform for disease modifying interventional strategies.
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http://dx.doi.org/10.1186/s12868-016-0304-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086065PMC
October 2016

Sex-related differences in reactivity of cerebral arterioles during moderate exercise training.

Microcirculation 2016 10;23(7):549-557

Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD, USA.

Objective: Our goals were to determine the influence of sex on reactivity of cerebral arterioles and whether MExT could influence sex-related differences in reactivity of cerebral arterioles.

Materials And Methods: Responses of cerebral arterioles were measured in Sed and MExT adult male and female Sprague-Dawley rats to eNOS-dependent (ADP), nNOS-dependent (NMDA), and NOS-independent (nitroglycerin) agonists before and following L-NMMA. In addition, protein expression for eNOS and nNOS was determined.

Results: NOS-dependent vasodilation was enhanced in Sed and MExT female rats compared to their male counterparts. L-NMMA produced a greater decrease in baseline diameter of arterioles in females compared to males, and produced less inhibition of NOS-dependent vasodilation in females. Expression of eNOS protein was significantly increased in Sed female when compared to Sed male rats; nNOS protein was similar in Sed males and females, but increased in MExT females.

Conclusions: The findings from this study indicate that while NOS-dependent vascular reactivity is increased in females, MExT does not alter vasodilation in males or females. These studies provide insights into the influence of sex and MExT on the cerebral microcirculation and may have implications regarding mechanisms that protect the brain in females compared to males.
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http://dx.doi.org/10.1111/micc.12306DOI Listing
October 2016

Smooth muscle-generated methylglyoxal impairs endothelial cell-mediated vasodilatation of cerebral microvessels in type 1 diabetic rats.

Br J Pharmacol 2016 12 14;173(23):3307-3326. Epub 2016 Oct 14.

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.

Background And Purpose: Endothelial cell-mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia-reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs).

Experimental Approach: Endothelial cell-mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia-reperfusion injury were assessed in brains of male Sprague-Dawley rats with streptozotocin-induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal-degrading enzyme glyoxalase-I (Glo-I) in cSMCs.

Key Results: After 7-8 weeks of T1D, endothelial cell-mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF-κB activity and TNF-α levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid-cerebral artery exacerbated ischaemia-reperfusion injury. In cSMCs, Glo-I protein was decreased, and the methylglyoxal-synthesizing enzyme, vascular adhesion protein 1 (VAP-1) and methylglyoxal were increased. Restoring Glo-I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP-1 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia-reperfusion injury and increased microvessel perfusion.

Conclusions And Implications: Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia-reperfusion injury in diabetic rats. Lowering methylglyoxal produced by cSMCs may be a viable therapeutic strategy to preserve cECs function and blunt deleterious downstream consequences in T1D.
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http://dx.doi.org/10.1111/bph.13617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738666PMC
December 2016

Chronic nicotine exposure exacerbates transient focal cerebral ischemia-induced brain injury.

J Appl Physiol (1985) 2016 Feb 10;120(3):328-33. Epub 2015 Dec 10.

Department of Cellular Biology and Anatomy, Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana

Tobacco smoking is a risk factor contributing to the development and progression of ischemic stroke. Among many chemicals in tobacco, nicotine may be a key contributor. We hypothesized that nicotine alters the balance between oxidant and antioxidant networks leading to an increase in brain injury following transient focal cerebral ischemia. Male Sprague-Dawley were treated with nicotine (2 or 4 mg·kg(-1)·day(-1)) for 4 wk via an implanted subcutaneous osmotic minipump and subjected to a 2-h middle cerebral artery occlusion (MCAO). Infarct size and neurological deficits were evaluated at 24 h of reperfusion. Superoxide levels were determined by lucigenin-enhanced chemiluminescence. Expression of oxidant and antioxidant proteins was measured using Western blot analysis. We found that chronic nicotine exposure significantly increased infarct size and worsened neurological deficits. In addition, nicotine significantly elevated superoxide levels of cerebral cortex under basal conditions. Transient focal cerebral ischemia produced an increase in superoxide levels of cerebral cortex in control group, but no further increase was found in the nicotine group. Furthermore, chronic nicotine exposure did not alter protein expression of NADPH oxidase but significantly decreased MnSOD and uncoupling protein-2 (UCP-2) in the cerebral cortex and cerebral arteries. Our findings suggest that nicotine-induced exacerbation in brain damage following transient focal cerebral ischemia may be related to a preexisting oxidative stress via decreasing of MnSOD and UCP-2.
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http://dx.doi.org/10.1152/japplphysiol.00663.2015DOI Listing
February 2016

Influence of type 1 diabetes on basal and agonist-induced permeability of the blood-brain barrier.

Physiol Rep 2015 Dec;3(12)

Department of Cellular Biology and Anatomy, LSU Health Sciences Center-Shreveport, Shreveport, Louisiana.

Type 1 diabetes mellitus (T1D) impairs endothelial nitric oxide synthase (eNOS)-dependent responses of cerebral arterioles. However, the influence of T1D on another critical aspect of endothelial cell function in the cerebral microcirculation, i.e., regulation of permeability of the blood-brain barrier (BBB), remains largely unknown. Our goal was to examine basal and agonist-induced changes in permeability of the BBB in nondiabetic and type 1 diabetic (streptozotocin; 50 mg/kg IP) rats. On the day of the experiment (2-3 months after streptozotocin), a craniotomy was made over the parietal cortex in nondiabetic and diabetic rats. We measured the permeability of the BBB (FITC-dextran-10K) under basal conditions and during application of histamine. We also measured diameter of cerebral arterioles in response to histamine in the absence and presence of NG-monomethyl-L-arginine (L-NMMA). We found that basal permeability of the BBB was elevated in T1D and application of histamine did not produce a further increase in permeability. In contrast, basal permeability of the BBB was minimal in nondiabetics and histamine produced an increase in permeability. In addition, histamine-induced arteriolar dilation was less in diabetics than in nondiabetics, and vasodilation to histamine was inhibited by L-NMMA. Our findings suggest that T1D-induced endothelial dysfunction leads to an increase in basal permeability of the BBB, but decreases the ability of the endothelium of the BBB to respond to an important inflammatory mediator. Thus, T1D impairs two critical aspects of endothelial cell function in the cerebral microcirculation, i.e., basal and agonist-induced changes in permeability of the BBB and arteriolar dilation.
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http://dx.doi.org/10.14814/phy2.12653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760440PMC
December 2015

Vigorous exercise training improves reactivity of cerebral arterioles and reduces brain injury following transient focal ischemia.

Microcirculation 2014 Aug;21(6):516-23

Department of Cellular Biology and Anatomy and the Center for Cardiovascular Diseases and Sciences, LSU Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.

Objective: Our objective was to examine whether vigorous exercise training (VExT) could influence nitric oxide synthase (NOS)-dependent vasodilation and transient focal ischemia-induced brain injury. Rats were divided into sedentary (SED) or VExT groups.

Materials And Methods: Exercise was carried out 5 days/week for a period of 8-10 weeks. First, we measured responses of pial arterioles to an eNOS-dependent (ADP), an nNOS-dependent (NMDA) and a NOS-independent (nitroglycerin) agonist in SED and VExT rats. Second, we measured infarct volume in SED and VExT rats following middle cerebral artery occlusion (MCAO). Third, we measured superoxide levels in brain tissue of SED and VExT rats under basal and stimulated conditions.

Results: We found that eNOS- and nNOS-dependent, but not NOS-independent vasodilation, was increased in VExT compared to SED rats, and this could be inhibited with L-NMMA in both groups. In addition, we found that VExT reduced infarct volume following MCAO when compared to SED rats. Further, superoxide levels were similar in brain tissue from SED and VExT rats under basal and stimulated conditions.

Conclusions: We suggest that VExT potentiates NOS-dependent vascular reactivity and reduces infarct volume following MCAO via a mechanism that appears to be independent of oxidative stress, but presumably related to an increase in the contribution of nitric oxide.
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http://dx.doi.org/10.1111/micc.12127DOI Listing
August 2014

Influence of exercise training on ischemic brain injury in type 1 diabetic rats.

J Appl Physiol (1985) 2012 Oct 2;113(7):1121-7. Epub 2012 Aug 2.

Department of Cellular Biology and Anatomy and the Center of Excellence in Cardiovascular Diseases and Sciences, Louisiana State University Health Science Center-Shreveport, Shreveport, LA, USA.

While exercise training (ExT) appears to influence cerebrovascular function during type 1 diabetes (T1D), it is not clear whether this beneficial effect extends to protecting the brain from ischemia-induced brain injury. Thus our goal was to examine whether modest ExT could influence transient focal ischemia-induced brain injury along with nitric oxide synthase (NOS)-dependent dilation of cerebral (pial) arterioles during T1D. Sprague-Dawley rats were divided into four groups: nondiabetic sedentary, nondiabetic ExT, diabetic (streptozotocin; 50 mg/kg ip) sedentary, and diabetic ExT. In the first series of studies, we measured infarct volume in all groups of rats following right MCA occlusion for 2 h, followed by 24 h of reperfusion. In a second series of studies, a craniotomy was performed over the parietal cortex, and we measured responses of pial arterioles to an endothelial NOS (eNOS)-dependent, a neuronal NOS (nNOS)-dependent, and a NOS-independent agonist in all groups of rats. We found that sedentary diabetic rats had significantly larger total, cortical, and subcortical infarct volumes following ischemia-reperfusion than sedentary nondiabetic, nondiabetic ExT, and diabetic ExT rats. Infarct volumes were similar in sedentary nondiabetic, ExT nondiabetic, and ExT diabetic rats. In contrast, ExT did not alter infarct size in nondiabetic compared with sedentary nondiabetic rats. In addition, ExT diabetic rats had impaired eNOS- and nNOS-dependent, but not NOS-independent, vasodilation that was restored by ExT. Thus ExT of T1D rats lessened ischemic brain injury following middle cerebral artery occlusion and restored impaired eNOS- and nNOS-dependent vascular function. Since the incidence of ischemic stroke is increased during T1D, we suggest that our finding are significant in that modest ExT may be a viable preventative therapeutic approach to lessen ischemia-induced brain injury that may occur in T1D subjects.
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http://dx.doi.org/10.1152/japplphysiol.00437.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774098PMC
October 2012

Low-dose alcohol consumption protects against transient focal cerebral ischemia in mice: possible role of PPARγ.

PLoS One 2012 27;7(7):e41716. Epub 2012 Jul 27.

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.

Background: We examined the influence of low-dose alcohol consumption on cerebral ischemia/reperfusion (I/R) injury in mice and a potential mechanism underlying the neuroprotective effect of low-dose alcohol consumption.

Methodology/principal Findings: C57BL/6 J mice were fed a liquid diet without or with 1% alcohol for 8 weeks, orally treated with rosiglitazone (20 mg/kg/day), a peroxisome proliferator-activated receptor gamma (PPARγ)-selective agonist, or GW9662 (3 mg/kg/day), a selective PPARγ antagonist, for 2 weeks. The mice were subjected to unilateral middle cerebral artery occlusion (MCAO) for 90 minutes. Brain injury, DNA fragmentation and nuclear PPARγ protein/activity were evaluated at 24 hours of reperfusion. We found that the brain injury and DNA fragmentation were reduced in 1% alcohol-fed mice compared to nonalcohol-fed mice. Rosiglitazone suppressed the brain injury in nonalcohol-fed mice, but didn't alter the brain injury in alcohol-fed mice. In contrast, GW9662 worsened the brain injury in alcohol-fed mice, but didn't alter the brain injury in nonalcohol-fed mice. Nuclear PPARγ protein/activity at peri-infarct and the contralateral corresponding areas of the parietal cortex was greater in alcohol-fed mice compared to nonalcohol-fed mice. Using differentiated catecholaminergic (CATH.a) neurons, we measured dose-related influences of chronic alcohol exposure on nuclear PPARγ protein/activity and the influence of low-dose alcohol exposure on 2-hour oxygen-glucose deprivation (OGD)/24-hour reoxygenation-induced apoptosis. We found that low-dose alcohol exposure increased nuclear PPARγ protein/activity and protected against the OGD/reoxygenation-induced apoptosis. The beneficial effect of low-dose alcohol exposure on OGD/reoxygenation-induced apoptosis was abolished by GW9662.

Conclusions/significance: Our findings suggest that chronic consumption of low-dose alcohol protects the brain against I/R injury. The neuroprotective effect of low-dose alcohol consumption may be related to an upregulated PPARγ.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041716PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407212PMC
April 2013

Exercise training improves the defective centrally mediated erectile responses in rats with type I diabetes.

J Sex Med 2011 Nov 24;8(11):3086-97. Epub 2011 Aug 24.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.

Introduction: Erectile dysfunction is a serious and common complication of diabetes mellitus. Apart from the peripheral actions, central mechanisms are also responsible for the penile erection.

Aim: The goal of the present study was to determine the impact of exercise training (ExT) on the centrally mediated erectile dysfunction in streptozotocin (STZ)-induced type I diabetic (T1D) rats.

Methods: Male Sprague-Dawley rats were injected with STZ to induce diabetes mellitus. Three weeks after STZ or vehicle injections, rats were assigned to either ExT (treadmill running for 3-4 weeks) or sedentary groups to produce four experimental groups: control + sedentary, T1D + sedentary, control + ExT, and T1D + ExT.

Main Outcome Measure: After 3-4 weeks ExT, central N-methyl-D-aspartic acid (NMDA) or sodium nitroprusside (SNP)-induced penile erectile responses were measured. Neuronal nitric oxide synthase (nNOS) expression in the paraventricular nucleus (PVN) of the hypothalamus was measured by using histochemistry, real time polymerase chain reaction (PCR) and Western blot approaches.

Results: In rats with T1D, ExT significantly improved the blunted erectile response, and the intracavernous pressure changes to NMDA (50 ng) microinjection within the PVN (T1D + ExT: 3.0 ± 0.6 penile erection/rat; T1D + sedentary: 0.5 ± 0.3 penile erection/rat within 20 minutes, P < 0.05). ExT improved erectile dysfunction induced by central administration of exogenous nitric oxide (NO) donor, SNP in T1D rats. Other behavior responses including yawning and stretching, induced by central NMDA and SNP microinjection were also significantly increased in T1D rats after ExT. Furthermore, we found that ExT restored the nNOS mRNA and protein expression in the PVN in T1D rats.

Conclusions: These results suggest that ExT may have beneficial effects on the erectile dysfunction in diabetes through improvement of NO bioavailability within the PVN. Thus, ExT may be used as therapeutic modality to up-regulate nNOS within the PVN and improve the central component of the erectile dysfunction in diabetes mellitus.
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http://dx.doi.org/10.1111/j.1743-6109.2011.02442.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204168PMC
November 2011

Chronic resveratrol treatment restores vascular responsiveness of cerebral arterioles in type 1 diabetic rats.

Am J Physiol Heart Circ Physiol 2011 Sep 10;301(3):H696-703. Epub 2011 Jun 10.

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, School of Medicine in Shreveport, Shreveport, Louisiana, USA.

Decreased dilation of cerebral arterioles via an increase in oxidative stress may be a contributing factor in the pathogenesis of diabetes-induced complications leading to cognitive dysfunction and/or stroke. Our goal was to determine whether resveratrol, a polyphenolic compound present in red wine, has a protective effect on cerebral arterioles during type 1 diabetes (T1D). We measured the responses of cerebral arterioles in untreated and resveratrol-treated (10 mg·kg(-1)·day(-1)) nondiabetic and diabetic rats to endothelial (eNOS) and neuronal (nNOS) nitric oxide synthase (NOS)-dependent agonists and to a NOS-independent agonist. In addition, we harvested brain tissue from nondiabetic and diabetic rats to measure levels of superoxide under basal conditions. Furthermore, we used Western blot analysis to determine the protein expression of eNOS, nNOS, SOD-1, and SOD-2 in cerebral arterioles and/or brain tissue from untreated and resveratrol-treated nondiabetic and diabetic rats. We found that T1D impaired eNOS- and nNOS-dependent reactivity of cerebral arterioles but did not alter NOS-independent vasodilation. While resveratrol did not alter responses in nondiabetic rats, resveratrol prevented T1D-induced impairment in eNOS- and nNOS-dependent vasodilation. In addition, superoxide levels were higher in brain tissue from diabetic rats and resveratrol reversed this increase. Furthermore, eNOS and nNOS protein were increased in diabetic rats and resveratrol produced a further increased eNOS and nNOS proteins. SOD-1 and SOD-2 proteins were not altered by T1D, but resveratrol treatment produced a decrease in SOD-2 protein. Our findings suggest that resveratrol restores vascular function and oxidative stress in T1D. We suggest that our findings may implicate an important therapeutic potential for resveratrol in treating T1D-induced cerebrovascular dysfunction.
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http://dx.doi.org/10.1152/ajpheart.00312.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191086PMC
September 2011

Dose-related influence of chronic alcohol consumption on cerebral ischemia/reperfusion injury.

Alcohol Clin Exp Res 2011 Jul 25;35(7):1265-9. Epub 2011 Feb 25.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Background: We examined the dose-related influence of alcohol consumption on cerebral ischemia/reperfusion (I/R) injury and the potential mechanism that accounts for the disparate effects of high-dose and low-dose alcohol consumption on cerebral I/R injury.

Methods: Sprague-Dawley rats were fed a liquid diet with or without 1, 3, 5, or 6.4% (v/v) alcohol for 8 weeks and subjected to a 2-hour middle cerebral artery occlusion (MCAO). We evaluated the brain injury at 24 hours of reperfusion. In addition, we measured protein expression of NMDA receptor and excitatory amino acid transporters (EAATs) in parietal cortex and the effect of NMDA receptor antagonist, memantine, on 2-hour MCAO/24 h reperfusion-induced brain injury.

Results: Compared with non-alcohol-fed rats, the total infarct volume was not altered in 3 and 5% alcohol-fed rats but significantly reduced in 1% alcohol-fed rats and exacerbated in 6.4% alcohol-fed rats. Expression of the NMDA receptor subunit, NR1, was upregulated in 6.4% alcohol-fed rats, whereas expression of EAAT2 was downregulated in 6.4% alcohol-fed rats and upregulated in 1% alcohol-fed rats. Memantine reduced 2-hour MCAO/24 h reperfusion-induced brain injury in non-alcohol-fed and 6.4% alcohol-fed rats, but not in 1% alcohol-fed rats. The magnitude of reduction in the brain injury was greater in 6.4% alcohol-fed rats compared to non-alcohol-fed rats.

Conclusions: Our findings suggest that chronic consumption of low-dose alcohol protects the brain against I/R injury, whereas chronic consumption of high-dose alcohol has detrimental effect on cerebral I/R injury. The disparate effects of low-dose and high-dose alcohol consumption on cerebral I/R may be related to an alteration in NMDA excitotoxicity.
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http://dx.doi.org/10.1111/j.1530-0277.2011.01461.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117087PMC
July 2011

Exercise training normalizes impaired NOS-dependent responses of cerebral arterioles in type 1 diabetic rats.

Am J Physiol Heart Circ Physiol 2011 Mar 17;300(3):H1013-20. Epub 2010 Dec 17.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.

Our goal was to examine whether exercise training (ExT) could normalize impaired nitric oxide synthase (NOS)-dependent dilation of cerebral (pial) arterioles during type 1 diabetes (T1D). We measured the in vivo diameter of pial arterioles in sedentary and exercised nondiabetic and diabetic rats in response to an endothelial NOS (eNOS)-dependent (ADP), an neuronal NOS (nNOS)-dependent [N-methyl-D-aspartate (NMDA)], and a NOS-independent (nitroglycerin) agonist. In addition, we measured superoxide anion levels in brain tissue under basal conditions in sedentary and exercised nondiabetic and diabetic rats. Furthermore, we used Western blot analysis to determine eNOS and nNOS protein levels in cerebral vessels/brain tissue in sedentary and exercised nondiabetic and diabetic rats. We found that ADP and NMDA produced a dilation of pial arterioles that was similar in sedentary and exercised nondiabetic rats. In contrast, ADP and NMDA produced only minimal vasodilation in sedentary diabetic rats. ExT restored impaired ADP- and NMDA-induced vasodilation observed in diabetic rats to that observed in nondiabetics. Nitroglycerin produced a dilation of pial arterioles that was similar in sedentary and exercised nondiabetic and diabetic rats. Superoxide levels in cortex tissue were similar in sedentary and exercised nondiabetic rats, were increased in sedentary diabetic rats, and were normalized by ExT in diabetic rats. Finally, we found that eNOS protein was increased in diabetic rats and further increased by ExT and that nNOS protein was not influenced by T1D but was increased by ExT. We conclude that ExT can alleviate impaired eNOS- and nNOS-dependent responses of pial arterioles during T1D.
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http://dx.doi.org/10.1152/ajpheart.00873.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064313PMC
March 2011

Enhanced angiotensin II-mediated central sympathoexcitation in streptozotocin-induced diabetes: role of superoxide anion.

Am J Physiol Regul Integr Comp Physiol 2011 Feb 17;300(2):R311-20. Epub 2010 Nov 17.

Dept. of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.

Studies have shown that the superoxide mechanism is involved in angiotensin II (ANG II) signaling in the central nervous system. We hypothesized that ANG II activates sympathetic outflow by stimulation of superoxide anion in the paraventricular nucleus (PVN) of streptozotocin (STZ)-induced diabetic rats. In α-chloralose- and urethane-anesthetized rats, microinjection of ANG II into the PVN (50, 100, and 200 pmol) produced dose-dependent increases in renal sympathetic nerve activity (RSNA), arterial pressure (AP), and heart rate (HR) in control and STZ-induced diabetic rats. There was a potentiation of the increase in RSNA (35.0 ± 5.0 vs. 23.0 ± 4.3%, P < 0.05), AP, and HR due to ANG II type I (AT(1)) receptor activation in diabetic rats compared with control rats. Blocking endogenous AT(1) receptors within the PVN with AT(1) receptor antagonist losartan produced significantly greater decreases in RSNA, AP, and HR in diabetic rats compared with control rats. Concomitantly, there were significant increases in mRNA and protein expression of AT(1) receptor with increased superoxide levels and expression of NAD(P)H oxidase subunits p22(phox), p47(phox), and p67(phox) in the PVN of rats with diabetes. Pretreatment with losartan (10 mg·kg(-1)·day(-1) in drinking water for 3 wk) significantly reduced protein expression of NAD(P)H oxidase subunits (p22(phox) and p47(phox)) in the PVN of diabetic rats. Pretreatment with adenoviral vector-mediated overexpression of human cytoplasmic superoxide dismutase (AdCuZnSOD) within the PVN attenuated the increased central responses to ANG II in diabetes (RSNA: 20.4 ± 0.7 vs. 27.7 ± 2.1%, n = 6, P < 0.05). These data support the concept that superoxide anion contributes to an enhanced ANG II-mediated signaling in the PVN involved with the exaggerated sympathoexcitation in diabetes.
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http://dx.doi.org/10.1152/ajpregu.00246.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051357PMC
February 2011

Exercise training restores impaired dilator responses of cerebral arterioles during chronic exposure to nicotine.

J Appl Physiol (1985) 2010 Oct 12;109(4):1109-14. Epub 2010 Aug 12.

Dept. of Cellular and Integrative Physiology, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA.

Our goal was to determine whether exercise training (ExT) alleviates impaired nitric oxide synthase (NOS)-dependent dilation of pial arterioles during chronic exposure to nicotine. We measured dilation of cerebral (pial) arterioles in sedentary and exercised control and nicotine-treated (2 mg·kg(-1)·day(-1) for 4 wk via an osmotic minipump) rats to an endothelial NOS (eNOS)-dependent (ADP), a neuronal NOS (nNOS)-dependent [N-methyl-D-aspartic acid (NMDA)], and a NOS-independent (nitroglycerin) agonist. In addition, we harvested brain tissue from sedentary and exercised control and nicotine-treated rats to measure the production of superoxide anion and measured superoxide dismutase-1 (SOD-1) protein in cerebral microvessels using Western blot. We found that eNOS-and nNOS-dependent, but not NOS-independent, vasodilation was impaired in nicotine-treated compared with control rats. In addition, the production of superoxide anion (lucigenin chemiluminescence) was increased, and SOD-1 protein decreased, in rats treated with nicotine compared with control rats. Further, although ExT did not significantly affect eNOS- or nNOS-dependent vasodilation in control rats, ExT restored impaired eNOS- and nNOS-dependent responses in nicotine-treated rats. In addition, the increase in superoxide anion production observed in nicotine-treated rats was reduced by ExT, and SOD-1 protein was increased in nicotine-treated rats by ExT. We suggest that ExT restores impaired NOS-dependent dilation of pial arterioles during chronic exposure to nicotine by a mechanism related to the formation of superoxide anion.
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http://dx.doi.org/10.1152/japplphysiol.00564.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963320PMC
October 2010

Inhibition of endothelin-1 receptors improves impaired nitric oxide synthase-dependent dilation of cerebral arterioles in type-1 diabetic rats.

Microcirculation 2010 Aug;17(6):439-46

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.

Objective: Endothelin-1 has been implicated in the pathogenesis of many cardiovascular-related diseases, including diabetes. The goal of this study was to examine the influence of endothelin-1 receptors (ET(A)) in impaired responses of cerebral (pial) arterioles in type-1 diabetic rats.

Methods: We measured responses of cerebral arterioles in non-diabetic rats to endothelial nitric oxide synthase (eNOS)-dependent (ADP), neuronal nitric oxide synthase (nNOS)-dependent (N-methyl-d-aspartic acid [NMDA]) and NOS-independent (nitroglycerin) agonists before and during application of BQ-123, an ET(A) receptor antagonist. In addition, we harvested brain tissue from non-diabetic and diabetic rats to measure the production of superoxide anion under basal conditions and during inhibition of ET(A) receptors.

Results: We found that diabetes specifically impaired eNOS- and nNOS-dependent reactivity of cerebral arterioles, but did not alter NOS-independent vasodilation. In addition, while BQ-123 did not alter responses in non-diabetic rats, BQ-123 restored impaired eNOS- and nNOS-dependent vasodilation in diabetic rats. Further, superoxide production was higher in brain tissue from diabetic rats compared with non-diabetic rats under basal conditions and BQ-123 decreased basal production of superoxide in diabetic rats.

Conclusion: We suggest that activation of ET(A) receptors during type-1 diabetes mellitus plays an important role in impaired eNOS- and nNOS-dependent dilation of cerebral arterioles.
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http://dx.doi.org/10.1111/j.1549-8719.2010.00042.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922043PMC
August 2010

Alcohol-induced exacerbation of ischemic brain injury: role of NAD(P)H oxidase.

Alcohol Clin Exp Res 2010 Nov;34(11):1948-55

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.

Background:  Chronic alcohol consumption increases ischemic stroke and exacerbates ischemic brain injury. We determined the role of NAD(P)H oxidase in exacerbated ischemic brain injury during chronic alcohol consumption.

Methods:  Sprague Dawley rats were fed a liquid diet with or without alcohol (6.4% v/v) for 8 weeks. We measured the effect of apocynin on 2-hour middle cerebral artery occlusion (MCAO)/24-hour reperfusion-induced brain injury. In addition, superoxide production and expression of NAD(P)H oxidase subunit, gp91phox, in the peri-infarct area were assessed.

Results: Chronic alcohol consumption produced a larger infarct volume, worse neurological score, and higher superoxide production. Acute (5 mg/kg, ip, 30 minutes before MCAO) and chronic treatment with apocynin (7.5 mg/kg/d in the diet, 4 weeks prior to MCAO) reduced infarct volume, improved neurological outcome, and attenuated superoxide production in alcohol-fed rats. Expression of gp91phox at basal conditions and following ischemia/reperfusion was greater in alcohol-fed rats compared to non-alcohol-fed rats. In addition, neurons are partially responsible for upregulated gp91phox during alcohol consumption.

Conclusions: Our findings suggest that NAD(P)H oxidase may play an important role in exacerbated ischemic brain injury during chronic alcohol consumption.
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http://dx.doi.org/10.1111/j.1530-0277.2010.01284.xDOI Listing
November 2010

Dynamic change of hydrogen sulfide during global cerebral ischemia-reperfusion and its effect in rats.

Brain Res 2010 Jul 15;1345:197-205. Epub 2010 May 15.

Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, PR China.

Hydrogen sulfide (H(2)S) is a gaseous messenger and serves as an important neuromodulator in central nervous system. In the current study, we investigated the change of H(2)S and cystathionine beta-synthase (CBS), an H(2)S-synthesizing enzyme at different time points of reperfusion following global cerebral ischemia in rats, and the effect of exogenous H(2)S on global cerebral ischemia-reperfusion injury. First, we used global cerebral ischemia-reperfusion model by occlusion of bilateral common carotid arteries and vertebral arteries. Next, we measured H(2)S levels in the hippocampus, cortex and plasma, the activity of H(2)S-synthesizing enzymes and expression of CBS mRNA and protein in the hippocampus and cortex at 12 h, 24 h, 48 h, 72 h and 7 days of reperfusion following 15 min cerebral ischemia. Second, we pretreated rats with different doses of sodium hydrogen sulfide (NaHS), an H(2)S donor and observed its effect on neuronal injury induced by 7 days of reperfusion after 15 min global cerebral ischemia. We found that when compared to sham group the amount of H(2)S in the hippocampus was increased significantly at 12 h of reperfusion after cerebral ischemia, markedly decreased at 24 h, restored to the same level as that in sham group at 48 h and maintained at 72 h and 7 days. The same change tendency in the levels of H(2)S was found in the cortex as described for the hippocampus. We found a similar change tendency in the activity of H(2)S-synthesizing enzymes, CBS mRNA and protein expression to that in the H(2)S level at different time points of reperfusion. Furthermore, while 180 micromol/kg NaHS pretreatment deteriorated the neuronal injury after global cerebral ischemia, 25 micromol/kg NaHS attenuated the neuronal injury. We suggest that a decrease of H(2)S level at 24 h of reperfusion after global cerebral ischemia may be involved in neuronal injury after cerebral ischemia and lower concentration rather than higher concentration of exogenous H(2)S may offer a protection against the neuronal injury induced by global cerebral ischemia-reperfusion.
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http://dx.doi.org/10.1016/j.brainres.2010.05.017DOI Listing
July 2010

Carbonylation of myosin heavy chains in rat heart during diabetes.

Biochem Pharmacol 2010 Jul 30;80(2):205-17. Epub 2010 Mar 30.

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, United States.

Cardiac inotropy progressively declines during diabetes mellitus. To date, the molecular mechanisms underlying this defect remain incompletely characterized. This study tests the hypothesis that ventricular myosin heavy chains (MHC) undergo carbonylation by reactive carbonyl species (RCS) during diabetes and these modifications contribute to the inotropic decline. Male Sprague-Dawley rats were injected with streptozotocin (STZ). Fourteen days later the animals were divided into two groups: one group was treated with the RCS blocker aminoguanidine for 6 weeks, while the other group received no treatment. After 8 weeks of diabetes, cardiac ejection fraction, fractional shortening, left ventricular pressure development (+dP/dt) and myocyte shortening were decreased by 9%, 16%, 34% and 18%, respectively. Ca(2+)- and Mg(2+)-actomyosin ATPase activities and peak actomyosin syneresis were also reduced by 35%, 28%, and 72%. MHC-alpha to MHC-beta ratio was 12:88. Mass spectrometry and Western blots revealed the presence of carbonyl adducts on MHC-alpha and MHC-beta. Aminoguanidine treatment did not alter MHC composition, but it blunted formation of carbonyl adducts and decreases in actomyosin Ca(2+)-sensitive ATPase activity, syneresis, myocyte shortening, cardiac ejection fraction, fractional shortening and +dP/dt induced by diabetes. From these new data it can be concluded that in addition to isozyme switching, modification of MHC by RCS also contributes to the inotropic decline seen during diabetes.
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http://dx.doi.org/10.1016/j.bcp.2010.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988575PMC
July 2010

Nitric oxide synthase-dependent responses of the basilar artery during acute infusion of nicotine.

Nicotine Tob Res 2009 Mar 23;11(3):270-7. Epub 2009 Feb 23.

Department of Cellular and Integrative Physiology, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA.

Introduction: Our goals were to determine whether acute exposure to nicotine alters nitric oxide synthase (NOS)-dependent responses of the basilar artery and to identify a potential role for activation of NAD(P)H oxidase in nicotine-induced impairment in NOS-dependent responses of the basilar artery.

Methods: We measured in vivo diameter of the basilar artery in response to NOS-dependent (acetylcholine) and NOS-independent (nitroglycerin) agonists before and during an acute infusion of nicotine (2 microg/kg/min intravenously for 30 min followed by a maintenance dose of 0.35 microg/kg/min). In addition, we measured superoxide anion production (lucigenin chemiluminescence) by the basilar artery in response to nicotine in the absence or presence of apocynin.

Results: We found that NOS-dependent, but not NOS-independent, vasodilation was impaired during infusion of nicotine. In addition, treatment of the basilar artery with apocynin (100 microM, 30 min prior to infusion of nicotine) prevented nicotine-induced impairment in NOS-dependent vasodilation. Further, the production of superoxide anion was increased in the basilar artery by nicotine, and this increase could be inhibited by apocynin.

Discussion: Our findings suggest that acute exposure to nicotine impairs NOS-dependent dilation of the basilar artery by a mechanism that appears to be related to the release of superoxide anion. A possible source of superoxide may be via the activation of NAD(P)H oxidase.
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http://dx.doi.org/10.1093/ntr/ntn025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666373PMC
March 2009

A modified suture technique produces consistent cerebral infarction in rats.

Brain Res 2008 Dec 24;1246:158-66. Epub 2008 Sep 24.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.

Intraluminal occlusion of the middle cerebral artery (MCA) is used extensively in cerebral ischemia research. We tested a modified nylon suture in a rat model of middle cerebral artery occlusion (MCAO) under two anesthesia regimens. Sprague-Dawley rats were divided into six groups (Group 1, Poly-L-lysine-coated suture under ketamine/xylazine anesthesia; Group 2, modified suture under ketamine/xylazine anesthesia; Group 3, Poly-L-lysine-coated suture under ketamine/xylazine anesthesia with mechanical ventilation; Group 4, modified suture under ketamine/xylazine anesthesia with mechanical ventilation; Group 5, Poly-L-lysine-coated suture under isoflurane anesthesia; Group 6, modified suture under isoflurane anesthesia) and subjected to 2-hour MCAO. Regional cerebral blood flow (rCBF) was monitored by Laser-Doppler flowmetry. Neurological evaluation and ischemic lesion (TTC stain) were assessed at 24 hours of reperfusion. The total ischemic lesion (sum of areas with lacking and intermediate TTC staining) was similar among all six groups. Compared with a Poly-L-lysine-coated suture technique, the modified suture technique produced a lower rCBF, larger infarct size, smaller variance of infarct size, and greater neurological deficit. In addition, isoflurane significantly reduced infarct size. We conclude that the use of this modified suture technique with ketamine/xylazine anesthesia and mechanical ventilation produces a more consistent change in cerebral ischemic damage following MCAO in rats.
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http://dx.doi.org/10.1016/j.brainres.2008.08.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963993PMC
December 2008

Losartan improves impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type 1 diabetic rats.

Brain Res 2008 May 21;1209:128-35. Epub 2008 Mar 21.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.

We examined whether activation of angiotensin-1 receptors (AT1R) could account for impaired responses of cerebral arterioles during type 1 diabetes (T1D). First, we measured responses of cerebral arterioles in nondiabetic rats to eNOS-dependent (acetylcholine and adenosine diphosphate (ADP)) and -independent (nitroglycerin) agonists before and during application of angiotensin II. Next, we examined whether losartan could improve impaired responses of cerebral arterioles during T1D. In addition, we harvested cerebral microvessels for Western blot analysis of AT1R protein and measured production of superoxide anion by brain tissue under basal conditions and in response to angiotensin II in the absence or presence of losartan. We found that angiotensin II specifically impaired eNOS-dependent reactivity of cerebral arterioles. In addition, while losartan did not alter responses in nondiabetics, losartan restored impaired eNOS-dependent vasodilatation in diabetics. Further, AT1R protein was higher in diabetics compared to nondiabetics. Finally, superoxide production was higher in brain tissue from diabetics compared to nondiabetics under basal conditions, angiotensin II increased superoxide production in nondiabetics and diabetics, and losartan decreased basal (diabetics) and angiotensin II-induced production of superoxide (nondiabetics and diabetics). We suggest that activation of AT1R during T1D plays a critical role in impaired eNOS-dependent dilatation of cerebral arterioles.
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http://dx.doi.org/10.1016/j.brainres.2008.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705945PMC
May 2008
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