Daily spontaneous running attenuated the central gain of the arterial baroreflex.
Animal; Animals; Arteries/*physiology; Baroreflex/*physiology; Brain/*physiology; Female; Male; Motor Activity/*physiology; Physical Conditioning; Rats; Sprague-Dawley
Exercise training attenuates arterial baroreflex function. Mechanisms responsible may include an attenuated aortic baroreceptor reactivity (afferent mechanisms) and/or an attenuated central baroreflex gain. We tested the hypothesis that the aortic baroreceptor reactivity and/or central gain is attenuated by daily spontaneous running (DSR). Eighteen anesthetized Sprague-Dawley rats (11 control and 7 DSR) were tracheotomized and instrumented with femoral venous and right carotid arterial catheters. Electrodes were placed around the left aortic depressor nerve and the lumbar sympathetic trunk. Eight to thirteen weeks of DSR were associated with a 20% increase in heart weight-to-body weight ratio (2.83 +/- 0.04 vs. 3.39 +/- 0.10 g/kg; P \textless 0.001) and resting bradycardia (413 +/- 6 vs. 384 +/- 10 beats/min; P = 0.01). DSR reduced the central gain of the baroreflex regulation of heart rate (0.210 +/- 0.046 vs. 0.005 +/- 0.021 beats.min-1.%-1; P = 0.004) during decreases in arterial pressure. However, the reactivity of aortic baroreceptor afferents and the central gain of the baroreflex control of lumbar sympathetic nerve activity were not different in control and DSR rats. Thus DSR reduced the central gain of the arterial baroreflex regulation of heart rate without changing the reactivity of aortic baroreceptor afferents. We conclude that afferent mechanisms are not responsible for the training-induced reduction in arterial baroreflex function.
Chen C Y; DiCarlo S E; Scislo T J
The American journal of physiology
1995
1995-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.1995.268.2.H662" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.1995.268.2.H662</a>
Role of endothelium in sexual dimorphism in vasopressin-induced contraction of rat aorta.
*Sex Characteristics; *Vasoconstriction; Animals; Aorta/*drug effects; Arginine Vasopressin/*pharmacology; Arginine/analogs & derivatives/pharmacology; Endothelium; Female; Indomethacin/pharmacology; Male; Nitric Oxide/antagonists & inhibitors; omega-N-Methylarginine; Osmolar Concentration; Phenylephrine/pharmacology; Rats; Sprague-Dawley; Vascular/*physiology
In rat thoracic aorta, contractile responses to arginine vasopressin (AVP) are twofold higher in females than in males. To determine the role of the endothelium in this phenomenon, the effects of endothelium removal and inhibition of nitric oxide (NO) synthase and cyclooxygenase were examined in thoracic aortas prepared from male and female Sprague-Dawley rats and mounted for isometric tension recording. Maximal contractile response to AVP was substantially higher in female (4,232 +/- 316 mg/mg ring dry wt) than in male aortas (1,365 +/- 239; P \textless 0.01). Removal of the endothelium markedly potentiated maximal response to AVP in male aortas (4,100 +/- 422 mg/mg ring wt; P \textless 0.01); endothelium removal increased sensitivity but not maximal response in female aortas. Inhibition of NO synthase with NG-monomethyl-L-arginine (L-NMMA, 250 microM) doubled maximal contraction to AVP in male aortas (3,175 +/- 193 mg/mg ring wt; P \textless 0.01); L-NMMA increased sensitivity but not maximal response in female aortas. Inhibition of cyclooxygenase with indomethacin (10 microM) did not alter maximal response to AVP in male aortas but significantly attenuated responses of female aortas (2,816 +/- 306 mg/mg ring wt; P \textless 0.01). In contrast, maximal contractile response to phenylephrine hydrochloride (PE) was 40% higher in males than in females (P \textless 0.01); L-NMMA increased both the sensitivity and maximal response to PE to a greater extent in female (3,061 +/- 121 vs. 4,971 +/- 135 mg/mg ring wt; P \textless 0.01) than in male aortas (4,317 +/- 227 vs. 4,899 +/- 104 mg/mg ring wt; P \textless 0.01). (ABSTRACT TRUNCATED AT 250 WORDS)
Stallone J N
The American journal of physiology
1993
1993-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.1993.265.6.H2073" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.1993.265.6.H2073</a>
Daily spontaneous running did not alter vagal afferent reactivity.
*Blood Pressure/drug effects; *Heart Rate/drug effects; *Physical Conditioning; Afferent Pathways/drug effects/*physiology; Analysis of Variance; Animal; Animals; Biguanides/pharmacology; Body Weight; Female; Heart/anatomy & histology/drug effects/*physiology; Hypoglycemic Agents/pharmacology; Organ Size; Rats; Sprague-Dawley; Time Factors; Vagus Nerve/drug effects/*physiology
Exercise training alters the cardiopulmonary baroreflex regulation of the circulation; however, the mechanisms responsible are unknown. One possibility is an enhanced afferent response to cardiopulmonary stimulation. We therefore tested the hypothesis that daily spontaneous running (DSR) would enhance cardiopulmonary vagal afferent responses to mechanical (increase in left atrial pressure, LAP) and chemical (phenyl biguanide, PBG) stimulation. Reactivity of single-fiber cardiopulmonary vagal afferents was evaluated in 16 control and 12 DSR anesthetized Sprague-Dawley rats. Rats were weaned at 3 wk of age and randomly assigned to a control or DSR group. Eight to twelve weeks of DSR was associated with a 27% increase in heart weight-to-body weight ratio (3.27 +/- 0.08 vs. 2.56 +/- 0.05 g/kg, P \textless 0.001) and resting bradycardia (394 +/- 10 vs. 421 +/- 8 beats/min, P = 0.036). However, DSR did not alter the stimulus-response curves to increases in LAP (frequency of discharge vs. LAP) for either the high-frequency (maximum response, sedentary 59.6 +/- 3.2, DSR 60.1 +/- 5.0 spikes/s) or low-frequency (maximum response, sedentary 20.0 +/- 2.9 DSR 20.6 +/- 3.9 spikes/s) receptors. Dose-response curves to chemical stimulation (spikes/s vs. PBG dose) were also not altered by DSR. Thus DSR did not change vagal afferent reactivity to mechanical or chemical stimulation.
Scislo T J; DiCarlo S E; Collins H L
The American journal of physiology
1993
1993-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.1993.265.5.H1564" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.1993.265.5.H1564</a>
Acute exercise enhances nitric oxide modulation of vascular response to phenylephrine.
*Physical Exertion; Animals; Arginine/analogs & derivatives/pharmacology; Blood Flow Velocity; Blood Pressure/drug effects; Blood Vessels/*drug effects; Dose-Response Relationship; Drug; Female; Heart Rate/drug effects; Iliac Artery/drug effects/physiology; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide/antagonists & inhibitors/*physiology; Phenylephrine/*pharmacology; Rats; Sprague-Dawley; Time Factors; Vasoconstriction/drug effects/physiology
The influence of the release of endothelium-derived nitric oxide (NO) on the vasoconstrictor response to phenylephrine (PE) was evaluated before and after a single bout of dynamic exercise. Each rat ran on a motor-driven treadmill at
Patil R D; DiCarlo S E; Collins H L
The American journal of physiology
1993
1993-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.1993.265.4.H1184" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.1993.265.4.H1184</a>
Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol.
70-kDa/metabolism; Angiotensin II/pharmacology; Animals; Antioxidants/*pharmacology; Cell Differentiation/drug effects; Cell Division/drug effects; Cells; Cultured; Drug Interactions; Epidermal Growth Factor/pharmacology; Fibroblasts/*cytology/*drug effects; Male; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Myocardium/*cytology; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins/metabolism; Rats; Resveratrol; Ribosomal Protein S6 Kinases; Signal Transduction/drug effects; Sprague-Dawley; Stilbenes/*pharmacology; Vasoconstrictor Agents/pharmacology
Cardiac fibroblasts (CFs) regulate myocardial remodeling by proliferating, differentiating, and secreting extracellular matrix proteins. Prolonged activation of CFs leads to cardiac fibrosis and reduced myocardial contractile function. Resveratrol (RES) exhibits a number of cardioprotective properties; however, the possibility that this compound affects CF function has not been considered. The current study tests whether RES directly influences the growth and proliferation of CFs and differentiation to the hypersecretory myofibroblast phenotype. Pretreatment of CFs with RES (5-25 microM) inhibited basal and ANG
Olson Erik R; Naugle Jennifer E; Zhang Xiaojin; Bomser Joshua A; Meszaros J Gary
American journal of physiology. Heart and circulatory physiology
2005
2005-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00763.2004" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00763.2004</a>
Type VI collagen induces cardiac myofibroblast differentiation: implications for postinfarction remodeling.
Angiotensin II/pharmacology; Animals; Cell Differentiation/*drug effects; Cell Proliferation/drug effects; Cells; Collagen Type I/physiology; Collagen Type III/physiology; Collagen Type VI/*physiology; Coronary Vessels/pathology; Cultured; Extracellular Matrix/*physiology; Fibroblasts/*cytology; Fibrosis/etiology; Ligation; Male; Myocardial Infarction/physiopathology; Rats; Sprague-Dawley; Ventricular Remodeling/*physiology
Cardiac fibroblast (CF) proliferation and differentiation into hypersecretory myofibroblasts can lead to excessive extracellular matrix (ECM) production and cardiac fibrosis. In turn, the ECM produced can potentially activate CFs via distinct feedback mechanisms. To assess how specific ECM components influence CF activation, isolated CFs were plated on specific collagen substrates (type I, III, and VI collagens) before functional assays were carried out. The type VI collagen substrate potently induced myofibroblast differentiation but had little effect on CF proliferation. Conversely, the type I and III collagen substrates did not affect differentiation but caused significant induction of proliferation (type I, 240.7 +/- 10.3%, and type III, 271.7 +/- 21.8% of basal). Type I collagen activated ERK1/2, whereas type III collagen did not. Treatment of CFs with angiotensin II, a potent mitogen of CFs, enhanced the growth observed on types I and III collagen but not on the type VI collagen substrate. Using an in vivo model of myocardial infarction (MI), we measured changes in type VI collagen expression and myofibroblast differentiation after post-MI remodeling. Concurrent elevations in type VI collagen and myofibroblast content were evident in the infarcted myocardium 20-wk post-MI. Overall, types I and III collagen stimulate CF proliferation, whereas type VI collagen plays a potentially novel role in cardiac remodeling through facilitation of myofibroblast differentiation.
Naugle Jennifer E; Olson Erik R; Zhang Xiaojin; Mase Sharon E; Pilati Charles F; Maron Michael B; Folkesson Hans G; Horne Walter I; Doane Kathleen J; Meszaros J Gary
American journal of physiology. Heart and circulatory physiology
2006
2006-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00321.2005" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00321.2005</a>
Sexual dimorphism in prostanoid-potentiated vascular contraction: roles of endothelium and ovarian steroids.
*Sex Characteristics; Animals; Aorta/drug effects/physiology; Bridged Bicyclo Compounds; Cyclooxygenase Inhibitors/pharmacology; Endothelium; Enzyme Inhibitors/pharmacology; Estrogens/*physiology; Fatty Acids; Female; Heterocyclic; Hydrazines/pharmacology; Imidazoles/pharmacology; Indomethacin/pharmacology; Male; Ovariectomy; Phenylephrine/pharmacology; Progesterone/*physiology; Prostaglandins/*metabolism; Rats; Sprague-Dawley; Thromboxanes/metabolism; Unsaturated; Vascular/*metabolism; Vasoconstriction/drug effects/*physiology; Vasoconstrictor Agents/pharmacology; Vasopressins/pharmacology
The effects of constrictor prostanoid (CP) pathway inhibitors on vascular reactivity to vasopressin (VP) and phenylephrine (PE) were examined in thoracic aortas of male, female, and ovariectomized (OVX) female Sprague-Dawley rats. Maximal contractile response of control (Cont) aortas to VP was markedly higher in females (3,885 +/- 332 mg/mg ring wt) than in males (810 +/- 148 mg). Indomethacin (Indo; 10 microM) attenuated maximal response to VP in females (3,043 +/- 277 mg) but not in males. SQ-29,548 (SQ; 1 microM) attenuated maximal response to VP in females (3,042 +/- 290 mg) to a similar extent as Indo. Dazoxiben (Daz; 10 microM) alone had no effect, but Daz + SQ attenuated maximal contractile response to VP to a similar extent as SQ alone. Removal of the endothelium in female aortas attenuated contractile responses to VP in Cont aortas. OVX attenuated maximal contractile response to VP in Cont aortas (2,093 +/- 329 mg) and abolished the attenuating effects of Indo. Indo, SQ, and Daz exerted identical effects on contractile responses of male, female, and OVX female aortas to PE. These findings establish the following in the rat aorta: 1) CP, probably thromboxane and/or endoperoxide, is responsible for approximately
Fulton Clifford T; Stallone John N
American journal of physiology. Heart and circulatory physiology
2002
2002-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00099.2002" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00099.2002</a>
Impact of type 1 diabetes on cardiac fibroblast activation: enhanced cell cycle progression and reduced myofibroblast content in diabetic myocardium.
Animals; Blood Glucose/metabolism; Blotting; Body Weight/physiology; Cell Cycle Proteins/biosynthesis; Cell Cycle/*physiology; Cell Differentiation/physiology; Cell Proliferation; Cell Separation; Diabetes Mellitus; Echocardiography; Experimental/pathology; Fibroblasts/*physiology; Male; Microarray Analysis; Myocardium/cytology/*pathology; Myofibroblasts/*physiology; Phenotype; Rats; RNA/biosynthesis/isolation & purification; Signal Transduction/physiology; Sprague-Dawley; Type 1/diagnostic imaging/*pathology; Western
Diabetic patients are prone to developing myocardial fibrosis and suffer from decreased wound healing capabilities. The purpose of this study was to determine whether diabetes alters cardiac fibroblast activity in the myocardium in a 6-wk streptozotocin-induced type 1 diabetic model. In vivo echocardiography indicated significant dilation of the left ventricle (LV) in the diabetic animals, while cardiac function was comparable to that in the normal group. We isolated cardiac fibroblasts from diabetic and control hearts and observed increased proliferation of the diabetic fibroblasts. Microarray analysis using mRNA collected from whole LVs revealed downregulation of known inhibitors of proliferation, p53 and p21, in the diabetic group, consistent with our proliferation data. Western blot analysis confirmed a reduction in p53 protein expression in the diabetic hearts compared with control. We explored the potential signaling underlying the downregulation of these cell cycle mediators and determined that activated Akt, a signal that inhibits p53, was elevated in the diabetic group. Surprisingly, the hearts from the diabetic group contained lower levels of the myofibroblast marker alpha-smooth muscle actin (alpha-SMA) and higher levels of desmin and platelet endothelial cell adhesion molecule (PECAM). The isolated fibroblasts from the diabetic group also contained significantly less alpha-SMA. These data suggest that early-stage diabetic hearts contain highly proliferative fibroblasts, which predisposes the diabetic myocardium to fibrosis, but have fewer myofibroblasts, which may compromise wound healing.
Shamhart Patricia E; Luther Daniel J; Hodson Ben R; Koshy John C; Ohanyan Vahagn; Meszaros J Gary
American journal of physiology. Endocrinology and metabolism
2009
2009-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpendo.00327.2009" target="_blank" rel="noreferrer noopener">10.1152/ajpendo.00327.2009</a>
Physiology laboratory experience for high school students.
*Laboratories; Adolescent; Animals; Dissection; Female; Humans; Male; Muscles/physiology; Ohio; Physiology/*education/instrumentation; Rats; Sprague-Dawley; Teaching/methods
Recently, we were charged with providing a learning opportunity for high school students participating in the Upward Bound Regional Math and Science Program, a program designed to stimulate interest in mathematics and science for students from disadvantaged environments. Our challenge was to introduce students to the joys, excitement, and mystery of physiology and to stimulate their interest for future study. To this end, we developed a laboratory experience that examined basic physiological concepts in an animal model. This opportunity introduced students to how their bodies work and the importance of the use of animals in research. The students left the experience confident, motivated, and excited about learning.
Collins H L; DiCarlo S E
The American journal of physiology
1993
1993-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/advances.1993.265.6.S47" target="_blank" rel="noreferrer noopener">10.1152/advances.1993.265.6.S47</a>
Hyperglycemia enhances function and differentiation of adult rat cardiac fibroblasts.
*Cell Differentiation; Animals; Blood Glucose/metabolism; cardiac fibroblast; Cell Movement; Cell Proliferation; Cells; collagen; Collagen/metabolism; collagene; concentration elevee de glucose; Cultured; diabete; diabetes; fibroblaste cardiaque; Fibroblasts/*metabolism/pathology; Fibrosis; high glucose; Hyperglycemia/*metabolism/pathology; Male; migration; Myocardium/*metabolism/pathology; myofibroblast; myofibroblastes; proliferation; Rats; Signal Transduction; Sprague-Dawley
Diabetes is an independent risk factor for cardiovascular disease that can eventually cause cardiomyopathy and heart failure. Cardiac fibroblasts (CF) are the critical mediators of physiological and pathological cardiac remodeling; however, the effects of hyperglycemia on cardiac fibroblast function and differentiation is not well known. Here, we performed a comprehensive investigation on the effects of hyperglycemia on cardiac fibroblasts and show that hyperglycemia enhances cardiac fibroblast function and differentiation. We found that high glucose treatment increased collagen I, III, and VI gene expression in rat adult cardiac fibroblasts. Interestingly, hyperglycemia increased CF migration and proliferation that is augmented by collagen I and III. Surprisingly, we found that short term hyperglycemia transiently inhibited ERK1/2 activation but increased AKT phosphorylation. Finally, high glucose treatment increased spontaneous differentiation of cardiac fibroblasts to myofibroblasts with increasing passage compared with low glucose. Taken together, these findings suggest that hyperglycemia induces cardiac fibrosis by modulating collagen expression, migration, proliferation, and differentiation of cardiac fibroblasts.
Shamhart Patricia E; Luther Daniel J; Adapala Ravi K; Bryant Jennifer E; Petersen Kyle A; Meszaros J Gary; Thodeti Charles K
Canadian journal of physiology and pharmacology
2014
2014-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1139/cjpp-2013-0490" target="_blank" rel="noreferrer noopener">10.1139/cjpp-2013-0490</a>
Local modulation of adrenergic responses in the hindlimb vasculature of the intact conscious rat.
Adrenergic Agonists/*pharmacology; Animals; Arginine/analogs & derivatives/pharmacology; Cyclooxygenase Inhibitors/pharmacology; Female; Hemodynamics/*drug effects/physiology; Hindlimb/*blood supply/drug effects/metabolism; Indomethacin/pharmacology; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase/antagonists & inhibitors; Rats; Sprague-Dawley
1. Local modulation of adrenergic responses was examined in the hindlimb vasculature of chronically instrumented intact conscious rats. Sprague-Dawley rats (n = 22) were instrumented with a Doppler flow probe around the right common iliac artery, a polyethylene catheter inserted just distal to the flow probe and a left carotid arterial catheter. 2. The effects of various concentrations of the alpha 1-adrenergic receptor agonist phenylephrine (0.005-0.075 microgram kg-1), the alpha 2-adrenergic receptor agonist clonidine (0.1-0.7 microgram kg-1), and the endogenous adrenergic receptor agonist adrenaline (0.02-0.08 microgram kg-1), were investigated under control conditions, and in the presence of the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester hydrochoride (L-NAME) (NO-X, 0.2 mg kg-1) and the cyclo-oxygenase inhibitor indomethacin (CO-X, 10 mg kg-1). Results were presented as dose-response curves. 3. Heart rate and arterial pressure were not altered by any of the agents because all were locally injected into the hindlimb vasculature and the selected doses were lower than those which elicited systemic responses. 4. Maximal vasoconstrictor responses to phenylephrine were enhanced in the presence of NO-X (50 +/- 6%) and
DiCarlo S E; Patil R D; Collins H L; Chen C Y
The Journal of physiology
1995
1995-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1113/jphysiol.1995.sp020771" target="_blank" rel="noreferrer noopener">10.1113/jphysiol.1995.sp020771</a>
Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress.
*ammonia; *ATP; *cellular respiration; *cirrhosis; *mitochondria; *Oxidative Stress; *portacaval anastamosis; *reactive oxygen species; *skeletal muscle; Adenosine Triphosphate/metabolism; Aged; Animals; Cell Line; Cell Respiration; Creatine Kinase/metabolism; Female; Humans; Hyperammonemia/*metabolism; Liver Cirrhosis/metabolism; Male; Middle Aged; Mitochondria; Muscle; Muscle/*metabolism; Myosin Heavy Chains/metabolism; NAD/metabolism; Rats; Reactive Oxygen Species/metabolism; Skeletal/*metabolism; Sprague-Dawley; Thiobarbituric Acid Reactive Substances/metabolism
KEY POINTS: Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia. We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD(+) /NADH ratio and ATP content. During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids. Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell-permeable ester of alphaKG reversed the lower TCA cycle intermediate concentrations and increased ATP content. Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS. ABSTRACT: Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non-hepatic ammonia disposal. Non-hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from alpha-ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD(+) /NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell-permeable ester of alpha-ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia-induced mitochondrial dysfunction is a novel therapeutic approach.
Davuluri Gangarao; Allawy Allawy; Thapaliya Samjhana; Rennison Julie H; Singh Dharmvir; Kumar Avinash; Sandlers Yana; Van Wagoner David R; Flask Chris A; Hoppel Charles; Kasumov Takhar; Dasarathy Srinivasan
The Journal of physiology
2016
2016-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1113/JP272796" target="_blank" rel="noreferrer noopener">10.1113/JP272796</a>
Selective Targeting of Heme Protein in Cytochrome P450 and Nitric Oxide Synthase by Diphenyleneiodonium.
*cytochrome P450; *flavoenzymes; *heme; *nitric oxide synthase; *reactive oxygen species; Animals; Cytochrome P-450 Enzyme Inhibitors/*pharmacology; Cytochrome P-450 Enzyme System/*metabolism; Dose-Response Relationship; Drug; Heme/*antagonists & inhibitors/metabolism; Humans; Liver/drug effects/enzymology; Mice; Microsomes; Nitric Oxide Synthase Type II/*antagonists & inhibitors/metabolism; Nitric Oxide/metabolism; Onium Compounds/*pharmacology; Rats; Recombinant Proteins/metabolism; Sprague-Dawley; Time Factors
Cytochrome P450 (CYP) enzymes mediate mixed-function oxidation reactions important in drug metabolism. The aromatic heterocyclic cation, diphenyleneiodonium (DPI), binds flavin in cytochrome P450 reductase and inhibits
Szilagyi John T; Mishin Vladimir; Heck Diane E; Jan Yi-Hua; Aleksunes Lauren M; Richardson Jason R; Heindel Ned D; Laskin Debra L; Laskin Jeffrey D
Toxicological sciences : an official journal of the Society of Toxicology
2016
2016-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/toxsci/kfw031" target="_blank" rel="noreferrer noopener">10.1093/toxsci/kfw031</a>
Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms.
*Phytotherapy; Alkylating Agents/toxicity; Animals; Antioxidants/*therapeutic use; Blotting; Carcinoma; Diethylnitrosamine/toxicity; Experimental/chemically induced/*drug therapy/metabolism; GA-Binding Protein Transcription Factor/*metabolism; gamma-Glutamyltransferase/metabolism; Hepatocellular/chemically induced/*drug therapy/metabolism; Immunoenzyme Techniques; Lipid Peroxidation/drug effects; Liver Neoplasms; Male; Oxidative Stress; Plant Extracts/*therapeutic use; Punicaceae/*chemistry; Rats; Sprague-Dawley; Western
Hepatocellular carcinoma (HCC), one of the most prevalent and lethal cancers, has shown an alarming rise in the USA. Without effective therapy for HCC, novel chemopreventive strategies may effectively circumvent the current morbidity and mortality. Oxidative stress predisposes to hepatocarcinogenesis and is the major driving force of HCC. Pomegranate, an ancient fruit, is gaining tremendous attention due to its powerful antioxidant properties. Here, we examined mechanism-based chemopreventive potential of a pomegranate emulsion (PE) against dietary carcinogen diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis that mimics human HCC. PE treatment (1 or 10 g/kg), started 4 weeks prior to the DENA challenge and continued for 18 weeks thereafter, showed striking chemopreventive activity demonstrated by reduced incidence, number, multiplicity, size and volume of hepatic nodules, precursors of HCC. Both doses of PE significantly attenuated the number and area of gamma-glutamyl transpeptidase-positive hepatic foci compared with the DENA control. PE also attenuated DENA-induced hepatic lipid peroxidation and protein oxidation. Mechanistic studies revealed that PE elevated gene expression of an array of hepatic antioxidant and carcinogen detoxifying enzymes in DENA-exposed animals. PE elevated protein and messenger RNA expression of the hepatic nuclear factor
Bishayee Anupam; Bhatia Deepak; Thoppil Roslin J; Darvesh Altaf S; Nevo Eviatar; Lansky Ephraim P
Carcinogenesis
2011
2011-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/carcin/bgr045" target="_blank" rel="noreferrer noopener">10.1093/carcin/bgr045</a>
Pomegranate exerts chemoprevention of experimentally induced mammary tumorigenesis by suppression of cell proliferation and induction of apoptosis.
*Punicaceae/chemistry; 10-Dimethyl-1; 2-benzanthracene; 9; Animal Studies; Animals; Anticarcinogenic Agents/*therapeutic use; Apoptosis; Apoptosis/*drug effects; Breast Neoplasms – Mortality; Breast Neoplasms – Prevention and Control; Breast Neoplasms – Risk Factors; Cell Physiology; Cell Proliferation/*drug effects; Diet – Evaluation; Experimental/pathology/*prevention & control; Female; Funding Source; Gene Expression Regulation; Genes; Human; Immunohistochemistry; Mammary Neoplasms; Mutation; National Institutes of Health (U.S.); Neoplasms – Prevention and Control; Phytotherapy; Pomegranate; Proto-Oncogene Proteins c-bcl-2/analysis; Rats; Sprague-Dawley; Tamoxifen; United States
Breast cancer is the second leading cause of cancer-related death in women in the United States and discovery and development of safe chemopreventive drugs is urgently needed. The fruit pomegranate (Punica granatum) is gaining importance because of its various health benefits. This study was initiated to investigate chemopreventive potential of a pomegranate emulsion (PE) against 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary carcinogenesis. The animals were orally administered with PE (0.2-5.0 g/kg), starting 2 wk before and 16 wk following DMBA treatment. PE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden, and reversed histopathological changes. PE dose-dependently suppressed cell proliferation and induced apoptosis in mammary tumors. Immunohistochemical studies showed that PE increased intratumor Bax, decreased Bcl2 and manifested a proapoptotic shift in Bax/Bcl2 ratio. In addition, our gene expression study showed PE-mediated upregulation of Bad, caspase-3, caspase-7, caspase-9, poly (ADP ribose) polymerase and cytochrome c in mammary tumors. Thus, PE exerts chemoprevention of mammary carcinogenesis by suppressing cell proliferation and inducing apoptosis mediated through upregulation of Bax and downregulation of Bcl2 in concert with caspase cascades. Pomegranate bioactive phytoconstituents could be developed as a chemopreventive drug to reduce the risk of breast cancer.
Bishayee Anupam; Mandal Animesh; Bhattacharyya Piyali; Bhatia Deepak
Nutrition and cancer
2016
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1080/01635581.2016.1115094" target="_blank" rel="noreferrer noopener">10.1080/01635581.2016.1115094</a>
Bcl-2 positively regulates Sox9-dependent chondrocyte gene expression by suppressing the MEK-ERK1/2 signaling pathway.
*Gene Expression Regulation; Adenoviridae/genetics; Animals; Apoptosis; beta-Galactosidase/metabolism; Blotting; Butadienes/pharmacology; Caspase Inhibitors; Cell Differentiation; Cell Line; Chondrocytes/*metabolism; Collagen Type II/metabolism; Down-Regulation; Enzyme Inhibitors/pharmacology; Fibroblasts/metabolism; Fluorescence; Genetic; High Mobility Group Proteins/*metabolism; Lac Operon; Luciferases/metabolism; MAP Kinase Kinase Kinases/*metabolism; Messenger/metabolism; Microscopy; Mitogen-Activated Protein Kinase 1/*metabolism; Mitogen-Activated Protein Kinase 3/*metabolism; NF-kappa B/metabolism; Nitriles/pharmacology; Phenotype; Phosphorylation; Promoter Regions; Protein Kinase C-alpha; Protein Kinase C/antagonists & inhibitors; Proteoglycans/metabolism; Proto-Oncogene Proteins c-bcl-2/*metabolism; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction; Small Interfering/metabolism; SOX9 Transcription Factor; Sprague-Dawley; Time Factors; Transcription; Transcription Factors/*metabolism; Transfection; Western
Bcl-2 is an anti-apoptotic protein that has recently been shown to regulate other cellular functions. We previously reported that Bcl-2 regulates chondrocyte matrix gene expression, independent of its anti-apoptotic function. Here, we further investigate this novel function of Bcl-2 and examine three intracellular signaling pathways likely to be associated with this function. The present study demonstrates that the activity of Sox9, a master transcription factor that regulates the gene expression of chondrocyte matrix proteins, is suppressed by Bcl-2 small interference RNA in the presence of caspase inhibitors. This effect was attenuated by prior exposure of chondrocytes to an adenoviral vector expressing sense Bcl-2. In addition, the down-regulation of Bcl-2, Sox9, and chondrocyte-specific gene expression by serum withdrawal in primary chondrocytes was reversed by expressing Bcl-2. Inhibition of the protein kinase C alpha and NFkappaB pathways had no effect on the maintenance of Sox9-dependent gene expression by Bcl-2. In contrast, whereas the MEK-ERK1/2 pathway negatively regulated the differentiated phenotype in wild type chondrocytes, inhibition of this pathway reversed the loss of differentiation markers and fibroblastic phenotype in Bcl-2-deficient chondrocytes. In conclusion, the present study identifies a specific signaling pathway, namely, MEK-ERK1/2, that is downstream of Bcl-2 in the regulation of Sox9-dependent chondrocyte gene expression and phenotype.
Yagi Rieko; McBurney Denise; Horton Walter E Jr
The Journal of biological chemistry
2005
2005-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/jbc.M502751200" target="_blank" rel="noreferrer noopener">10.1074/jbc.M502751200</a>
Orphan nuclear receptor oestrogen-related receptor gamma (ERRgamma) plays a key role in hepatic cannabinoid receptor type 1-mediated induction of CYP7A1 gene expression.
Animals; bile acid; Bile Acids and Salts/metabolism; Cannabinoid; cannabinoid receptors; CB1/agonists/genetics/*metabolism; Cells; Cholesterol 7-alpha-Hydroxylase/*biosynthesis/genetics; cholesterol 7alpha-hydroxylase (CYP7A1); Cultured; Cytoplasmic and Nuclear/metabolism; Drug Inverse Agonism; Estrogen/genetics/*metabolism; Ethanol/pharmacology; Gene Expression; Genetic; Glycerides/pharmacology; GSK5182; HEK293 Cells; Hepatocytes/metabolism; Humans; Inbred C57BL; Knockout; Liver/*metabolism; Mice; oestrogen-related receptor gamma (ERRgamma); orphan nuclear receptor; Promoter Regions; Rats; Receptor; Receptors; small heterodimer partner (SHP); Sprague-Dawley; Transcription
Bile acids are primarily synthesized from cholesterol in the liver and have important roles in dietary lipid absorption and cholesterol homoeostasis. Detailed roles of the orphan nuclear receptors regulating cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis, have not yet been fully elucidated. In the present study, we report that oestrogen-related receptor gamma (ERRgamma) is a novel transcriptional regulator of CYP7A1 expression. Activation of cannabinoid receptor type 1 (CB1 receptor) signalling induced ERRgamma-mediated transcription of the CYP7A1 gene. Overexpression of ERRgamma increased CYP7A1 expression in vitro and in vivo, whereas knockdown of ERRgamma attenuated CYP7A1 expression. Deletion analysis of the CYP7A1 gene promoter and a ChIP assay revealed an ERRgamma-binding site on the CYP7A1 gene promoter. Small heterodimer partner (SHP) inhibited the transcriptional activity of ERRgamma and thus regulated CYP7A1 expression. Overexpression of ERRgamma led to increased bile acid levels, whereas an inverse agonist of ERRgamma, GSK5182, reduced CYP7A1 expression and bile acid synthesis. Finally, GSK5182 significantly reduced hepatic CB1 receptor-mediated induction of CYP7A1 expression and bile acid synthesis in alcohol-treated mice. These results provide the molecular mechanism linking ERRgamma and bile acid metabolism.
Zhang Yaochen; Kim Don-Kyu; Lee Ji-Min; Park Seung Bum; Jeong Won-Il; Kim Seong Heon; Lee In-Kyu; Lee Chul-Ho; Chiang John Y L; Choi Hueng-Sik
The Biochemical journal
2015
2015-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1042/BJ20141494" target="_blank" rel="noreferrer noopener">10.1042/BJ20141494</a>
Estrogen differentially modulates nicotine-evoked dopamine release from the striatum of male and female rats.
Animals; Corpus Striatum/drug effects/*metabolism; Dopamine/*metabolism; Estradiol/*pharmacology; Female; In Vitro Techniques; Kinetics; Male; Nicotine/*pharmacology; Orchiectomy; Ovariectomy; Rats; Sex Characteristics; Sprague-Dawley
In the present experiment we examined the effects of an in vitro infusion of nicotine (10 microM) upon dopamine release from superfused striatum of castrated male and female rats treated or not treated with estrogen. Estrogen exerted bidirectional effects on nicotine-evoked dopamine release as a function of the sex of the animal. Nicotine-evoked dopamine release was increased in estrogen treated females and decreased in estrogen treated males. Peak nicotine-evoked dopamine output from estrogen treated females was significantly greater than that of estrogen treated males. These results may be related to the gender differences in response to nicotine and smoking behavior.
Dluzen D E; Anderson L I
Neuroscience letters
1997
1997-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0304-3940(97)00487-4" target="_blank" rel="noreferrer noopener">10.1016/s0304-3940(97)00487-4</a>
Castration increases nisoxetine-evoked norepinephrine levels in vivo within the olfactory bulb of male rats.
Animal/drug effects/physiology; Animals; Atomoxetine Hydrochloride; Extracellular Space/metabolism; Fluoxetine/*analogs & derivatives/*pharmacology; Male; Microdialysis; Norepinephrine Plasma Membrane Transport Proteins; Norepinephrine/*metabolism; Olfactory Bulb/drug effects/*metabolism; Orchiectomy/*adverse effects; Presynaptic Terminals/drug effects/metabolism; Propylamines/pharmacology; Rats; Reproduction/*physiology; Sexual Behavior; Smell/drug effects/physiology; Sprague-Dawley; Symporters/antagonists & inhibitors/*metabolism; Testosterone/*deficiency/metabolism; Up-Regulation/drug effects/physiology
In the present experiment we compared differences in extracellular norepinephrine levels in vivo within the olfactory bulb of intact and castrated male rats following infusion of the norepinephrine transport inhibitors, nisoxetine and tomoxetine. With this approach it was possible to assess whether dynamic changes in in vivo norepinephrine transporter function occur as a function of the gonadal state of the animal. Norepinephrine levels following infusion of nisoxetine were significantly increased in castrated compared with intact male rats. While a similar trend was present in response to tomoxetine infusion, these differences failed to achieve a statistically significant difference. These results demonstrate that castration of male rats alters norepinephrine transporter function within the olfactory bulbs. The increased extracellular levels of norepinephrine in response to agents which inhibit transporter function suggest that castration reduces transporter activity. Such effects have important implications not only with regard to processes involving the norepinephrine system in the olfactory bulb but also to the generalized sites and mechanisms by which gonadal steroid hormones modulate central nervous system functions.
Shang Yili; Dluzen Dean E
Neuroscience letters
2002
2002-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0304-3940(02)00412-3" target="_blank" rel="noreferrer noopener">10.1016/s0304-3940(02)00412-3</a>
Substance P in the uterine cervix, dorsal root ganglia and spinal cord during pregnancy and the effect of estrogen on SP synthesis.
Afferent/metabolism; Animals; Cervix Uteri/cytology/*metabolism; Down-Regulation; Estradiol/*analogs & derivatives/pharmacology; Estrogen/antagonists & inhibitors; Estrogens/*pharmacology; Female; Fulvestrant; Ganglia; Immunohistochemistry; In Situ Hybridization; Messenger/genetics/metabolism; Neurons; Postpartum Period; Pregnancy/*metabolism; Radioimmunoassay; Rats; Receptors; Reverse Transcriptase Polymerase Chain Reaction; RNA; Spinal Cord/cytology/*metabolism; Spinal/cytology/*metabolism; Sprague-Dawley; Substance P/*biosynthesis/genetics/metabolism; Up-Regulation
Prior to parturition the non-pliable uterine cervix undergoes a ripening process ("softens" and dilates) to allow a timely passage of the fetus at term. The exact mechanism(s) triggering and involved in cervical ripening are unknown, though evidence for a role for sensory neurons and their contained neuropeptides is emerging. Moreover, an apparent increase in neuropeptide immunoreactive nerves occurs in the cervix during pregnancy, maternal serum estrogen levels rise at term and uterine cervix-related L6-S1 dorsal root ganglia (DRG) sensory neurons express estrogen receptor (ER) and neuropeptides. Thus, we sought to test the hypothesis that the neuropeptide substance P (SP) changes biosynthesis and release over pregnancy, that estrogen, acting via the ER pathway, increases synthesis of SP in DRG, and that SP is utilized in cervical ripening at late pregnancy. Using immunohistochemistry, in situ hybridization, reverse transcriptase-polymerase chain reaction (RT-PCR) and radioimmunoassay (RIA), we investigated coexpression of ER-alpha/beta and SP; differential expression of
Mowa C N; Usip S; Storey-Workley M; Amann R; Papka R
Peptides
2003
2003-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0196-9781(03)00120-7" target="_blank" rel="noreferrer noopener">10.1016/s0196-9781(03)00120-7</a>
Calcitonin gene-related peptide-receptor component protein expression in the uterine cervix, lumbosacral spinal cord, and dorsal root ganglia.
Animals; Calcitonin Gene-Related Peptide/*biosynthesis/immunology/metabolism; Cervix Uteri/*metabolism; Female; Ganglia; Lumbosacral Region; Rats; Receptors; Spinal Cord/*metabolism; Spinal/*metabolism; Sprague-Dawley; Uterus/metabolism
The neuropeptide calcitonin gene-related peptide (CGRP) may play a role in neurogenic inflammation, tissue remodeling of the uterine cervix, promoting vasodilation, parturition, and processing of sensory information in the spinal cord. CGRP-immunoreactive nerves of the cervix and spinal cord have been studied but cellular identification of the CGRP receptor has received little attention.
Pokabla M J; Dickerson I M; Papka R E
Peptides
2002
2002-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0196-9781(01)00638-6" target="_blank" rel="noreferrer noopener">10.1016/s0196-9781(01)00638-6</a>
Sensory nerves and neuropeptides in uterine cervical ripening.
Animal; Animals; Calcitonin Gene-Related Peptide/biosynthesis; Capsaicin/pharmacology; Cervical Ripening/*metabolism; Cervix Uteri/*innervation/*metabolism; Complementary/metabolism; Female; Genetic; Immunohistochemistry; Labor; Messenger/metabolism; Neurokinin-1/biosynthesis; Neurons/metabolism; Neuropeptides/*biosynthesis; Nitric Oxide Synthase/biosynthesis; Obstetric; Plasmids/metabolism; Postpartum Period; Pregnancy; Rats; Receptors; RNA; Secretogranin II; Sprague-Dawley; Substance P/biosynthesis; Transcription
At the time of parturition (fetal delivery) the uterine cervix must "ripen," becoming soft, pliable, and dilated to accommodate the fetus' delivery. The fundamental processes underlying cervical ripening remain poorly understood. Knowledge that abundant autonomic and sensory nerves supply the uterine cervix, that transection of afferent nerves supplying the cervix blocks parturition, and that some of the changes in the cervix resemble those seen in inflammatory reactions suggests nerves may have a role in the cervical ripening changes. The present study utilized immunohistochemistry, plasma extravasation, and solution hybridization-nuclease protection assay to elucidate the complement of primary afferent nerves and some receptors in the rat cervix during pregnancy, and to determine if they may have roles in the ripening process at term. This study revealed an abundance of nerves associated with the cervical vasculature and myometrial smooth muscle containing immunoreactivity for substance P, calcitonin gene-related peptide, secretoneurin, and nitric oxide synthase throughout pregnancy. Many of these are small unmyelinated capsaicin-sensitive C-fibers. Substance P- (NK1-) and calcitonin gene-related peptide receptors were apparent on uterine cervix vasculature from pregnant, parturient, and postpartum rats. NK1 receptor mRNA was maximal at 20 days of pregnancy. Plasma extravasation of i.v. administered Evans Blue or Monastral Blue was most pronounced at parturition (shortly after NK1 mRNA is maximal); this was similar to plasma extravasation evoked by i.v. administration of substance P or capsaicin-treatment. This study revealed new data about the nervous system of the rat uterine cervix and that these nerves and their transmitters could very well be part of a neurogenic inflammatory process involved in cervical ripening.
Collins J J; Usip S; McCarson K E; Papka R E
Peptides
2002
2002-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0196-9781(01)00593-9" target="_blank" rel="noreferrer noopener">10.1016/s0196-9781(01)00593-9</a>
Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine.
Amygdala/*physiopathology; Animals; Association Learning/*physiology; Brain Mapping; Cerebral/*physiology; Classical/physiology; Cocaine-Related Disorders/*physiopathology; Conditioning; Dominance; Dopamine/physiology; Extinction; Male; Motivation; Psychological/physiology; Rats; Reinforcement Schedule; Self Administration; Sprague-Dawley; Substance Withdrawal Syndrome/*physiopathology
This study investigated the ability of bilateral excitotoxic lesions of the basolateral amygdala (BLA) to disrupt cocaine self-administration, responding during extinction sessions, and stimulus cued recovery of extinguished responding in rats. BLA and sham lesions following 7 days of 3 h limited access cocaine self-administration sessions (0.33 mg/infusion) on a fixed ratio 1 (FR1) schedule of reinforcement failed to alter cocaine intake and responding on 7 subsequent days of self-administration. This lack of effect suggests that the BLA is not paramount for the maintenance of cocaine's reinforcing effects. In contrast, BLA lesions, but not sham lesions, following 7 to 14 days of cocaine self-administration attenuated responding on a lever associated with cocaine infusions on the first day of extinction sessions and blocked the ability of drug associated stimuli to reinstate extinguished responding following 20 daily extinction sessions. However, lesions of the BLA did not attenuate stimulus cued recovery of responding following 43 days of withdrawal. These results are consistent with the hypothesis that the BLA is important for the conditioned incentive properties of reinforcers, but not primary reinforcement itself.
Meil W M; See R E
Behavioural brain research
1997
1997-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0166-4328(96)02270-x" target="_blank" rel="noreferrer noopener">10.1016/s0166-4328(96)02270-x</a>
Secure cranial-mount intrathecal cannulation - a spinal administration technique in the rat.
Analgesics; Anesthesia; Animals; Dose-Response Relationship; Drug; Injections; Microinjections; Morphine/administration & dosage/pharmacology; Opioid/administration & dosage/pharmacology; Rats; Spinal Cord/*physiology; Spinal/*instrumentation; Sprague-Dawley; Stereotaxic Techniques/*instrumentation
In order to identify an acute spinally mediated pharmacological effect of a bioactive substance, without incurring untoward supraspinal effects, it is necessary to administer the agent locally onto the spinal cord. The procedure delineated herein presents a modern technique to install a stable, permanent indwelling thecal cannulae with a cranially mounted aperture, and details a simple, repeatable administration system. These methods facilitate a quick, noninvasive spinal drug microadministration that is most useful for differentiation of the locus of pharmacological action without the behavioral disruption associated with other administration methodologies.
Schechter J B; Crisp T
Journal of neuroscience methods
2000
2000-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0165-0270(00)00161-8" target="_blank" rel="noreferrer noopener">10.1016/s0165-0270(00)00161-8</a>
Strain differences in neuropathic hyperalgesia.
Animals; Chronic Disease; Cytokines/physiology; Hyperalgesia/*etiology; Inbred F344; Inbred Lew; Ligation; Male; Rats; Sciatic Nerve/physiology; Species Specificity; Sprague-Dawley; Wistar
The purpose of this study was to investigate strain-related differences in the onset and maintenance of thermal hyperalgesia following the induction of peripheral nerve injury in two inbred strains of rats (Fischer 344 and Lewis) and two outbred strains of rats (Sprague-Dawley and Wistar). Neuropathic pain was induced via unilateral ligation of the left sciatic nerve with chromic gut sutures. A plantar analgesia meter was used to measure paw-withdrawal latency from the ligated vs. unligated hind paws of inbred vs. outbred strains of rats to investigate strain-related differences in nerve injury-induced thermal hyperalgesia. The results demonstrated no significant effects of animal strain on presurgical paw-withdrawal latency values. Following the sciatic nerve ligation (SNL) surgery, a significant hyperalgesic response was elicited from the Sprague-Dawley and Wistar rats (outbred strains) for at least 28 days. Conversely, data analyses from the inbred strains failed to demonstrate significant hyperalgesic responses to peripheral nerve injury, with the exception of postsurgical day 10. These data emphasize the importance of considering the strain of the rat being investigated before extrapolating the results from animals experiments to treatment strategies for humans with chronic neuropathic pain.
Lovell J A; Stuesse S L; Cruce W L; Crisp T
Pharmacology, biochemistry, and behavior
2000
2000-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0091-3057(99)00180-x" target="_blank" rel="noreferrer noopener">10.1016/s0091-3057(99)00180-x</a>
MDMA-like stimulus effects of hallucinogens in male Fawn-Hooded rats.
4-methylenedioxyamphetamine/*pharmacology; Animals; Central Nervous System Stimulants/*pharmacology; Conditioning; Cues; Discrimination (Psychology)/drug effects; Dopamine Agents/pharmacology; Dose-Response Relationship; Drug; Generalization; Hallucinogens/*pharmacology; Inbred Strains; Male; N-Methyl-3; Operant/drug effects; Rats; Serotonin Agents/pharmacology; Serotonin/genetics/physiology; Sprague-Dawley; Stimulus/drug effects
A two-lever, food-motivated, operant technique was employed to train the purportedly serotonergically dysfunctional Fawn-Hooded (FH) rat to discriminate 1.5 mg/kg MDMA. Once all 10 male subjects learned the MDMA-vehicle discrimination at criterion performance level, doses different than the training dose were used to generate a dose-response discrimination gradient. The ED50 value of MDMA was shown to be 0.136 mg/kg, not significantly different from that of previously trained Sprague-Dawley male rats. Thus, the Fawn-Hooded rat appears to not differ in its sensitivity to lower doses of MDMA. Testing for MDMA-like stimulus generalizations with other drugs indicated that the MDMA derivative MDE produced generalization at a dose of 2.25 mg/kg and allowed for an ED50 value of 0.496 mg/kg. Like MDE, the testing of alpha-ethyltryptamine was shown to produce
Schechter M D
Pharmacology, biochemistry, and behavior
1998
1998-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0091-3057(97)00415-2" target="_blank" rel="noreferrer noopener">10.1016/s0091-3057(97)00415-2</a>
Rohypnol ("roofies") control of drug discrimination: effect of coadministered ethanol or flumenazil.
Animals; Anti-Anxiety Agents/*pharmacology; Discrimination Learning/*drug effects; Dose-Response Relationship; Drug; Drug Administration Schedule; Ethanol/*pharmacology; Flumazenil/*pharmacology; Flunitrazepam/*pharmacology; GABA Antagonists/*pharmacology; Male; Rats; Sprague-Dawley
The benzodiazepine flunitrazepam (Rohypnol) was employed to control differentially discriminative performance in 10 Sprague-Dawley rats on a food-motivated FR10 schedule. The training dose was 2.5 mg/kg, and 20 min was employed between intraperitoneal administration and training; both values were employed in this study, which, in reality, is the first time in the drug discrimination literature for the training of this drug. Dose-response experiments indicated decreasing discriminative performance in concert with decreasing time to reach FR10 lever selection as the dose tested decreased from 2.5 to 0.04 mg/kg. The calculated ED50 for discriminative performance, i.e., lever selection of the drug-correct lever, was 0.076 mg/kg. The relatively few sessions needed to reach discrimination criterion, and the fact that the ED50 value was 1/33 of the training dose, suggests that a lower dose of Rohypnol may be used in the future to train rats in this paradigm. Time course experiments indicate decreasing discriminative performance from 20-240 min postadministration with a calculated half-life of 162.3 min. Administration of 450, 600, and 900 mg/kg ethanol (10% w/v) I.P. produced saline-like discriminative responding, whereas the combination of these doses with the 0.08 mg/kg Rohypnol dose produced increasing discriminative performance with the highest ethanol dose producing 72.2% Rohypnol-appropriate lever selections in a mean time to attain lever selection on the FR10 schedule of 12.8 s. These results suggest that a lower training dose of Rohypnol may allow for testing of a smaller ED50 Rohypnol dose with ethanol to produce a more complete generalization. The ability of flumenazil (Ro 15-1788) to dose dependently block the discrimination of Rohypnol suggests that this benzodiazepine produces its action by its agonistic efficacy at these receptors. The coadministration of Rohypnol and ethanol as a popular drug combination in humans is discussed, and evidence is offered as to their synergistic interactions in rat discrimination.
Schechter M D
Pharmacology, biochemistry, and behavior
1998
1998-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0091-3057(97)00309-2" target="_blank" rel="noreferrer noopener">10.1016/s0091-3057(97)00309-2</a>
Daily exercise reduces fat, protein and body mass in male but not female rats.
*Body Mass Index; Adipose Tissue/*metabolism; Animals; Body Composition/*physiology; Body Weight/physiology; Energy Metabolism/*physiology; Female; Gonadal Steroid Hormones/physiology; Male; Physical Exertion/*physiology; Proteins/*metabolism; Rats; Sex Characteristics; Sprague-Dawley
This study was designed to compare the estimated energy balance, linear growth (body and bone lengths) and body composition (all components including body mass, total body water, fat, protein and ash) response to daily spontaneous running (DSR) in young male and female rats. We tested the hypothesis that due to gender differences in energy efficiency, DSR would reduce linear growth and body composition more in male rats. Fourteen male and sixteen female weanling Sprague-Dawley rats were randomly assigned to either a sedentary (SED) control (male 7, female 8) or DSR (male 7, female 8) group. The DSR rats were allowed to run spontaneously in running wheels while SED rats remained in standard rat cages for 9 weeks. Body mass, running distance and food intake were measured over the nine week period. Subsequently, chemical analysis was performed to measure carcass content of water, protein, fat and ash. Linear growth was assessed by measures of body and bone lengths. The estimated energy balance of the DSR rats was computed and compared between genders. Estimated energy balance was significantly more negative in females than males due to significantly greater DSR distance. Body and bone lengths were similar among the SED and DSR female and SED and DSR male rats. However, whole body mass, fat mass and protein mass were significantly lower only in DSR males. These results demonstrate that DSR reduced body mass, body fat and protein mass in male rats but not in female rats despite a more negative estimated energy balance in female rats. These findings suggest that females are better protected from an energy deficit due to DSR. Possible mechanisms include gender-specific hormonal responses.
Cortright R N; Chandler M P; Lemon P W; DiCarlo S E
Physiology & behavior
1997
1997-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0031-9384(97)00148-0" target="_blank" rel="noreferrer noopener">10.1016/s0031-9384(97)00148-0</a>
Serotonergic mediation of fenfluramine discriminative stimuli in fawn-hooded rats.
*Discrimination Learning; 4-methylenedioxyamphetamine/pharmacology; Animals; Dose-Response Relationship; Drug; Fenfluramine/administration & dosage/*pharmacology; Fluoxetine/pharmacology; Ibogaine/pharmacology; Male; Methoxydimethyltryptamines/pharmacology; N-Methyl-3; Piperazines/pharmacology; Quipazine/pharmacology; Rats; Serotonin Agents/administration & dosage/*pharmacology; Serotonin Receptor Agonists/pharmacology; Serotonin/*metabolism; Sprague-Dawley
Fenfluramine, a drug that induces increased synaptic serotonin, was used to train Fawn-Hooded rats in a drug discrimination paradigm. This strain of rats is thought to possess a genetic serotonin storage abnormality. The intent of the study was to see if the Fawn-Hooded rat was similar or dissimilar to the more frequently used strain of Sprague-Dawley rat in its ability to learn to discriminate 2.0 mg/kg fenfluramine administered intraperitoneally. In addition, drugs presumed to work upon central serotonergic neurons were given to the fenfluramine-trained Fawn-Hooded rats to investigate if the cueing properties of the training drug generalized to other agents. Results indicate that the Fawn-Hooded rats learn to discriminate fenfluramine from its vehicle at the same rate, and with a similar sensitivity to lower doses, as do the Sprague-Dawley rats. Furthermore, fenfluramine was shown to completely generalize to MDMA (over 90%); TFMPP, m-CPP, quipazine and fluoxetine produced intermediate results (over 70%) and 5-MeODMT and ibogaine were vehicle-like (less than 70%). As these results coincide with those previously found in Sprague-Dawley rats, the conclusion is that the functional capacity to discriminate fenfluramine appears to be like that of other rat lines, and serotonergically-mediated, in the Fawn-Hooded rat. Suggestions to explain these results are offered and discussed.
Schechter M D
Life sciences
1997
1905-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0024-3205(96)00668-6" target="_blank" rel="noreferrer noopener">10.1016/s0024-3205(96)00668-6</a>
Phentermine+fenfluramine produce cocaine-like discriminative cues.
*Discrimination (Psychology); Animals; Cocaine/*pharmacology; Dose-Response Relationship; Drug; Fenfluramine/administration & dosage/*pharmacology; Male; Phentermine/administration & dosage/*pharmacology; Rats; Sprague-Dawley
Drug discrimination studies were conducted in six male Sprague-Dawley rats trained to discriminate the interoceptive cues produced by 10 mg/kg cocaine in an effort to investigate if there is stimulus generalization to phentermine or phentermine + fenfluramine. Once having reached criterion performance, these rats were tested with lower doses of cocaine and generated a typical dose-response curve allowing for calculation of an ED50 value: 2.798 mg/kg. Testing of phentermine in doses of 1.25-5.0 mg/kg indicated generalization with the highest dose producing 80% cocaine-appropriate responding and allowing for an ED50 value of 2.356 mg/kg. When the phentermine doses were tested in combination 2.0 mg/kg fenfluramine, however, there was an increase in the discriminability of the highest phentermine dose and a slight decrease in the ED50 value of the combination. Thus, administration of phentermine + fenfluramine, having both dopamine-releasing and serotonin-releasing properties, respectively, may mimic the neurochemical activity by which cocaine acts in the central nervous system and may possibly allow for cocaine-like effects as these two drugs see increased use in obesity control.
Schechter M D; McBurney D
Life sciences
1996
1905-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0024-3205(96)00513-9" target="_blank" rel="noreferrer noopener">10.1016/s0024-3205(96)00513-9</a>
Sex differences in extracellular and intracellular calcium-mediated vascular reactivity to vasopressin in rat aorta.
*Sex Characteristics; 1; 3-Pyridinecarboxylic acid; 4-dihydro-2; 6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-; Animals; Aorta/drug effects/*metabolism; Calcium Channel Agonists/*pharmacology; Calcium Channel Blockers/*pharmacology; Calcium/*metabolism; Diltiazem/pharmacology; Dose-Response Relationship; Drug; Female; In Vitro Techniques; Male; Methyl ester/pharmacology; Potassium Chloride/pharmacology; Rats; Simvastatin/pharmacology; Sprague-Dawley; Vasoconstriction/*drug effects; Vasopressins/*metabolism
In rat thoracic aorta, contractile responses to arginine vasopressin are two-fold higher in females than in males. To determine the roles of extracellular and intracellular Ca2+ in this sexual dimorphism in vascular function, vascular reactivity and Ca2+ channel function were examined in thoracic aortae of male and female rats. In the presence of diltiazem (10 microM), maximal contraction to vasopressin was reduced to a greater extent in male (65+/-2%) than in female aortae (38+/-1%). Maximal contractile responses to KCl and Bay K 8644 were similar in male and female aortae. Sensitivity to KCI was slightly but significantly higher in male than in female aorta; in contrast, sensitivity to Bay K 8644 was nearly three-fold higher in males than in females. Removal of the endothelium enhanced sensitivity to KCl similarly in male and female aortae. In the presence of simvastatin (60 microM; an inhibitor of intracellular Ca2+ release), reactivity to vasopressin was reduced substantially in female (42+/-1%) but unaltered in male aortae. Removal of the endothelium enhanced the inhibitory effect of simvastatin in both female (73+/-2%) and male aortae (41+/-2%). These findings demonstrate that male aortae depend more upon extracellular Ca2+ influx, whereas female aortae depend more upon intracellular Ca2+ release for vasopressin-induced contraction.
Eatman D; Stallone J N; Rutecki G W; Whittier F C
European journal of pharmacology
1998
1998-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0014-2999(98)00700-6" target="_blank" rel="noreferrer noopener">10.1016/s0014-2999(98)00700-6</a>
Discrete versus cumulative dosing in dose-response discrimination studies.
4-methylenedioxyamphetamine/*pharmacology; Animals; Chemical; Cocaine/*pharmacology; Discrimination Learning/*drug effects; Dose-Response Relationship; Drug; Drug Administration Schedule; Drug Evaluation; Male; N-Methyl-3; Preclinical; Rats; Sprague-Dawley; Stimulation
This study describes the results of a 'side-by-side' comparison of two measurement techniques and two dosing regimens in a discrimination study using rats trained to either 10 mg/kg cocaine or 2 mg/kg 3,4-methylenedioxymethamphetamine (MDMA). The measurements employed were either quantal or quantitative; the former an all-or-none correct lever selection measure and the latter a measure of all responses made at the time that the criterion for selection was met. The dosing regimens were either a discrete single injection of lower doses than used in training or a cumulative dose administration sequence, in an ascending order, during one session on two separate occasions. Results indicate that the cumulative dose-response relationships, as indicated by both the slope of the curve or the generated ED50 value, for the discrete and cumulative dose response curves do not significantly differ. In addition, both the quantal and quantitative measurements yield almost identical ED50 values, thus allowing for accurate comparability of drug-discrimination data using different techniques. The present experimentation employed two drugs known to produce heightened response rates which would not allow for behavioral suppression at the highest doses used either in discrete or cumulative regimens. The pharmacokinetics of the two drugs employed in the discrimination tests are considered and discussed in light of the advantages and disadvantages of each of the two methods employed.
Schechter M D
European journal of pharmacology
1997
1997-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0014-2999(97)85404-0" target="_blank" rel="noreferrer noopener">10.1016/s0014-2999(97)85404-0</a>
The effects of nicotine on dopamine and DOPAC output from rat striatal tissue.
3; 4-Dihydroxyphenylacetic Acid/*metabolism; Amphetamine/pharmacology; Animals; Central Nervous System Stimulants/pharmacology; Corpus Striatum/*drug effects/*metabolism; Dopamine/*metabolism; Dose-Response Relationship; Drug; Ganglionic Stimulants/administration & dosage/*pharmacology; Male; Nicotine/administration & dosage/*pharmacology; Potassium Chloride/pharmacology; Rats; Sprague-Dawley
The effects of varying doses of nicotine infusion upon spontaneous (basal) and subsequent potassium chloride-stimulated dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) output from superfused corpus striatal tissue fragments of male rats were tested. Spontaneous dopamine and DOPAC outputs were increased in response to 1, 5 and 10, but not to 0.1 and 0 (control) microM concentrations of nicotine. Interestingly, the subsequent K+-stimulated (30 mM) dopamine output was completely abolished in preparations infused with the 5 and 10 microM nicotine, but not with the 1 or 0.1 microM nicotine. No overall significant differences in K+-stimulated DOPAC were obtained among the five doses. In experiment 2, the effects of an initial infusion of amphetamine (10 microM), potassium chloride (30 mM), nicotine (10 microM) or normal superfusion medium (control) were compared upon subsequent K+-evoked dopamine release. The amount of dopamine released in response to the second (subsequent) infusion of K+ was significantly greater in the potassium chloride and control conditions versus the nicotine and amphetamine stimulated groups. No overall differences in DOPAC output were observed among the four conditions of experiment 2. These results demonstrate that nicotine can exert differential modulatory effects upon striatal dopaminergic activity as a function of the dose. The augmented levels of DOPAC output along with the abolition of the K+-stimulated dopamine release in response to the 5 and 10 microM nicotine doses suggest that these doses may simultaneously produce an activation of intraneuronal metabolism of dopamine to DOPAC along with an activation of release and inhibition of uptake to diminish stores available for subsequent responses to K+ stimulation.
Dluzen D E; Anderson L I
European journal of pharmacology
1998
1998-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0014-2999(97)01438-6" target="_blank" rel="noreferrer noopener">10.1016/s0014-2999(97)01438-6</a>
Olanzapine attenuates the reinforcing effects of cocaine.
Animal/*drug effects; Animals; Antipsychotic Agents/administration & dosage/*pharmacology; Behavior; Benzodiazepines; Cocaine/administration & dosage/antagonists & inhibitors/*pharmacology; Conditioning; Dopamine Uptake Inhibitors/administration & dosage/*pharmacology; Dose-Response Relationship; Drug; Food Preferences/drug effects; Male; Olanzapine; Operant/*drug effects; Pirenzepine/administration & dosage/*analogs & derivatives/pharmacology; Rats; Self Administration; Sprague-Dawley
The possibility that the atypical neuroleptic olanzapine can antagonize the ability of cocaine to produce both conditioned place preference and self-administration in rats was investigated. Pre-treatment with olanzapine (3.0, 4.5 mg/kg, but not 1.5 mg/kg) significantly attenuated conditioned place preference produced by cocaine (10 mg/kg). However, the higher dose of olanzapine administered alone resulted in conditioned place aversion. Pre-treatment with olanzapine also produced a dose-dependent decrease in cocaine self-administration (0.33 mg/infusion) under a fixed-ratio 2 schedule of reinforcement. Olanzapine produced a similar dose-responsive attenuation in operant responding for food (fixed-ratio 10) suggesting that olanzapine produces a nonspecific decrease in operant behavior. Pre-treatment with 4.5 mg/kg olanzapine significantly attenuated cocaine-induced hyperactivity, whereas lower olanzapine doses had little effect upon cocaine-induced hyperactivity. These results suggest that pre-treatment with olanzapine is capable of blocking the reinforcing effects of cocaine and illustrates the value of using multiple tests of reinforcement when evaluating the pharmacological effects of newer psychotherapeutic agents.
Meil W M; Schechter M D
European journal of pharmacology
1997
1997-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0014-2999(97)01351-4" target="_blank" rel="noreferrer noopener">10.1016/s0014-2999(97)01351-4</a>
Use of in vitro superfusion to assess the dynamics of striatal dopamine clearance: influence of estrogen.
Animals; Corpus Striatum/drug effects/*physiology; Dopamine/*metabolism/pharmacology; Estradiol/*pharmacology; Female; Kinetics; Nomifensine/*pharmacology; Ovariectomy; Rats; Sprague-Dawley
To determine the feasibility of assessing dopamine uptake using in vitro superfusion, striatal tissue from ovariectomized female rats was infused with dopamine (1 microM), nomifensine (1 mM), or a combination of dopamine and nomifensine. Treatment with nomifensine or dopamine/nomifensine increased the recovery of dopamine in the effluent samples as compared to treatment with dopamine alone. In Experiment 2, the striatal tissue was treated with varying concentrations (0, 3, 30 or 300 nM) estradiol throughout the superfusion and subsequently given a dopamine (1 microM) challenge. The recovery of dopamine was enhanced in the presence of 3 and 30 nM estradiol. These results show that (1) in vitro superfusion can be used to dynamically evaluate dopamine recovery, and (2) estradiol, like nomifensine, increases the recovery of exogenously applied dopamine from the striata of ovariectomized female rats. Such increases in dopamine recovery with estrogen and similarities to that obtained with nomifensine suggest that estrogen may be inhibiting dopamine uptake from these striatal tissue fragments. Moreover, the doses at which estrogen can exert these effects insinuates a physiological role for this process. Our data provide a clear functional demonstration for one of the mechanisms by which estradiol can modulate striatal dopamine neurons, that of an uptake inhibitor. Such a mechanism has important implications with regard to estradiol's capacity to function as a neuroprotectant of the nigrostriatal dopaminergic system through inhibition of uptake of neurotoxins which can produce neurodegeneration of striatal dopamine neurons.
Disshon K A; Dluzen D E
Brain research
1999
1999-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0006-8993(99)01863-6" target="_blank" rel="noreferrer noopener">10.1016/s0006-8993(99)01863-6</a>
Castration reduces olfactory bulb norepinephrine transporter function as indicated by responses to noradrenergic uptake blockers.
*Symporters; Adrenergic Uptake Inhibitors/*pharmacology; Animals; Atomoxetine Hydrochloride; Carrier Proteins/*metabolism; Infusions; Isotonic Solutions; Male; Norepinephrine Plasma Membrane Transport Proteins; Norepinephrine/*metabolism; Olfactory Bulb/*metabolism; Orchiectomy; Parenteral; Propylamines/pharmacology; Rats; Sprague-Dawley; Testis/*physiology; Thiophenes/pharmacology
It has been demonstrated that castration alters the functioning of the olfactory bulb (OB)-norepinephrine (NE) system. In the present experiment, we examined one of the mechanisms by which castration modulates the OB-NE system by comparing NE uptake activity between intact and castrated male rats as studied using an in vitro superfusion technique. To accomplish this goal, NE output from the OB of intact and castrated male rats in response to infusion with two different drugs which alter NE uptake functions, tomoxetine and talsupram, were tested. Overall, NE outputs in response to tomoxetine were significantly higher in the castrated than in intact rats and both groups were significantly greater than non-infused controls. For the talsupram infusion group, NE outputs from the castrated, but not intact rats, were significantly greater than controls. No statistically significant differences were detected between the castrated and intact rats. These results demonstrate that castration alters the NE uptake activities in response to these noradrenergic uptake blockers and suggest that one mechanism by which castration alters OB-NE functioning is through reducing the uptake activity of NE within the OB. Such findings have important implications for olfactory-based learning and memory/recognition processes which are believed to involve the OB-NE system and are altered following castration.
Shang Y; Dluzen D E
Brain research
1998
1998-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0006-8993(97)01101-3" target="_blank" rel="noreferrer noopener">10.1016/s0006-8993(97)01101-3</a>
Estrogen as a neuromodulator of MPTP-induced neurotoxicity: effects upon striatal dopamine release.
*MPTP Poisoning; 1-Methyl-4-phenylpyridinium/toxicity; Animals; Dopamine Agents/*toxicity; Dopamine/*metabolism; Estradiol/pharmacology; Estrogens/*physiology; Female; Neostriatum/drug effects/*metabolism; Neurotransmitter Agents/*physiology; Ovariectomy; Rats; Sprague-Dawley
The effects of estrogen upon MPTP-induced neurotoxicity were examined using in vitro superfusion. In Experiment 1, striatal tissue from ovariectomized rats was infused with MPP+ (10 microM), a combination of MPP+ and 17beta-estradiol (300 nM), the same dose of estradiol preceding MPP+, or no treatment infusion. The effects of these treatments on dopamine release rates during the infusion periods were determined. Infusion of MPP+ resulted in a significant increase in dopamine release as compared to the control. Estradiol added to the MPP+ infusion significantly attenuated this dopamine (DA) release, while estradiol treatment preceding the MPP+ had no effect. In Experiment 2, three different doses of estradiol (0.3, 3, or 300 nM) were infused simultaneously with the MPP+. Doses of estradiol below 300 nM did not attenuate the DA release. In Experiment 3, estradiol alone (300 nM) was infused, to determine dopamine release rate effects of the hormone itself. There was no difference between estradiol treated and non-infused control groups. These results demonstrate that the gonadal steroid hormone estradiol can modulate responses of striatal dopamine neurons to MPP+ by altering the immediate increase in dopamine release which occurs in response to this neurotoxin. These modulating effects of estradiol are dose-dependent, and represent a direct effect upon striatal neurons, most likely involving a non-genomic mechanism of action. These results implicate that hormonal modulation of nigrostriatal dopaminergic neurotoxicity may represent an important variable responsible for the sex differences which are reported in Parkinson's disease.
Disshon K A; Dluzen D E
Brain research
1997
1997-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0006-8993(97)00418-6" target="_blank" rel="noreferrer noopener">10.1016/s0006-8993(97)00418-6</a>
Estrogen reduces acute striatal dopamine responses in vivo to the neurotoxin MPP+ in female, but not male rats.
*Sex Characteristics; 1-Methyl-4-phenylpyridinium/*toxicity; 3; 4-Dihydroxyphenylacetic Acid/metabolism; Animals; Corpus Striatum/*metabolism; Dopamine/*metabolism; Estrogens/*pharmacology; Extracellular Space/metabolism; Female; Herbicides/*toxicity; Male; Microdialysis; Nerve Degeneration/chemically induced/metabolism; Parkinson Disease; Rats; Secondary/chemically induced/metabolism; Sprague-Dawley
The effects of in vivo estrogen treatment upon MPP(+)-induced dopamine (DA) release were determined using in vivo microdialysis in female and male rats. Ovariectomized female rats were implanted or not with an estrogen pellet (0.1 mg, 17beta estradiol) and subjected to microdialysis 6 days later. After baseline DA release was determined, 5 mM MPP(+) was infused through the microdialysis probe for one 20-min interval. Perfusion resumed with normal medium for the duration of the experiment. A significant attenuation of MPP(+)-induced DA release was obtained in estrogen-treated females. One week later, striatal DA and dihydroxyphenylacetic acid (DOPAC) concentrations were determined for the lesioned and non-lesioned striata of each animal. MPP(+) infusion significantly decreased striatal DA concentrations, however, there was no effect of estrogen treatment on striatal DA depletion. This experiment was repeated using orchidectomized male rats treated with 0, 0.1, or 5 mg estradiol. In contrast to the females, no differences in MPP(+)-induced DA release were seen among these males, and there was no significant effect of the varying estrogen treatments on striatal DA or DOPAC concentrations. These results demonstrate that in vivo estrogen treatment attenuates MPP(+)-induced striatal DA release in gonadectomized female, but not male, rats.
Disshon K A; Dluzen D E
Brain research
2000
2000-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0006-8993(00)02329-5" target="_blank" rel="noreferrer noopener">10.1016/s0006-8993(00)02329-5</a>
Phosphatidylinositide 3-kinase regulates angiotensin II-induced cytosolic phospholipase A2 activity and growth in vascular smooth muscle cells.
Angiotensin II/*metabolism; Animals; Arachidonic Acid/metabolism; Arachidonic Acids/pharmacology; Blotting; Cells; Chromones/pharmacology; Cultured; Enzyme Inhibitors/pharmacology; Flavonoids/pharmacology; Group IV Phospholipases A2; Male; Mitogen-Activated Protein Kinases/metabolism; Morpholines/pharmacology; Muscle; Phosphatidylinositol 3-Kinases/*physiology; Phospholipases A/*metabolism; Phospholipases A2; Phosphorylation; Rats; Smooth; Sprague-Dawley; Vascular/drug effects/*growth & development; Western
Angiotensin (Ang) II via the AT(1) receptor acts as a mitogen in vascular smooth muscle cells (VSMC) through stimulation of multiple signaling mechanisms, including tyrosine kinases and mitogen-activated protein kinase (MAPK). In addition, cytosolic phospholipase A(2)(cPLA(2))-dependent release of arachidonic acid (AA) is linked to VSMC growth and we have reported that Ang II stimulates cPLA(2) activity via the AT(1) receptor. The coupling of Ang II to the activation of cPLA(2) appears to involve mechanisms both upstream and downstream of MAPK such that AA stimulates MAPK activity which phosphorylates cPLA(2) to further enhance AA release. However, the upstream mechanisms responsible for activation of cPLA(2) are not well-defined. One possibility includes phosphatidylinositide
Silfani Tonous N; Freeman Ernest J
Archives of biochemistry and biophysics
2002
2002-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/S0003-9861(02)00066-8" target="_blank" rel="noreferrer noopener">10.1016/S0003-9861(02)00066-8</a>
The effect of intermittent-release intraperitoneal chemotherapy on wound healing.
Animals; Antineoplastic Agents/administration & dosage/*pharmacology; Carboplatin/administration & dosage/*pharmacology; Infusions; Laparotomy; Male; Paclitaxel/administration & dosage/*pharmacology; Parenteral; Rats; Sprague-Dawley; Tissue Adhesions/chemically induced; Wound Healing/*drug effects
OBJECTIVE: Our purpose was to study the effect on wound healing when intraperitoneal chemotherapy was instilled on a daily basis. STUDY DESIGN: Intraperitoneal carboplatin, Taxol, or saline solution was instilled daily into 70 rats after they underwent laparotomy. The animals were killed and analyzed for adhesions. An area measuring 5 x 5 cm including the incision was also harvested for biomechanical testing. The wound thickness was measured, and the Shore Western Materials Testing System (Monrovia, Calif.) was used to test the force required to break the wound, the stress, and the stiffness. RESULTS: Groups of 10 rats received saline solution control, carboplatin 6 mg/kg, 7 mg/kg, 8 mg/kg, or Taxol 2.5 mg/kg, 3.0 mg/kg, or 3.5 mg/kg. The total dose was divided into seven equal amounts, administered daily. No significant adhesions developed in any of the animals. The carboplatin group experienced no significant decrease in wound thickness whereas the higher-dose Taxol group had a significant decrease in thickness from 1.06 mm to 0.72 mm (p = 0.02). The wound-breaking strength (force) also decreased for the highest-dose Taxol group from 710 gm to 411 gm (p = 0.02). The wound stiffness was also decreased from 69 gm/mm to 46 gm/mm (p = 0.01). The other measured parameters for both the Taxol and carboplatin groups were not significantly decreased when compared with those of controls. CONCLUSION: The immediate instillation of divided daily carboplatin did not influence wound strength whereas the use of Taxol on a similar schedule significantly decreased wound strength.
Hopkins M P; von Gruenigen V E; Holda S; Weber B
American journal of obstetrics and gynecology
1997
1997-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0002-9378(97)70606-9" target="_blank" rel="noreferrer noopener">10.1016/s0002-9378(97)70606-9</a>