PHARMACOLOGYPHARMACOLOGYThe Journal of

And Experimental Therapeutics

A Publication of the American Society for

Pharmacology and Experimental Therapeutics

Edited for the Society by Rick G. Schnellmann

Volume 324 ■ Number 3 ■ March 2008 ■ ISSN 0022-3565

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PERSPECTIVES IN PHARMACOLOGYNAD� and Vitamin B3: From Metabolism to Therapies Anthony A. Sauve 883

CARDIOVASCULAR□S Functional Antagonism between Endogenous Neuropeptide Y

and Calcitonin Gene-Related Peptide in Mesenteric ResistanceArteries

Jo G. R. De Mey, Remco Megens, andGregorio E. Fazzi

930

□S Characterization of Epoxyeicosatrienoic Acid Binding Site inU937 Membranes Using a Novel Radiolabeled Agonist, 20-125I-14,15-Epoxyeicosa-8(Z)-Enoic Acid

Wenqi Yang, Venugopal Raju Tuniki,Siddam Anjaiah, J. R. Falck,Cecilia J. Hillard, and William B. Campbell

1019

Inhibiting Protease-Activated Receptor 4 Limits MyocardialIschemia/Reperfusion Injury in Rat Hearts by UnmaskingAdenosine Signaling

Jennifer L. Strande, Anna Hsu, Jidong Su,Xiangping Fu, Garrett J. Gross, andJohn E. Baker

1045

Characterization of the Molecular Fragment That IsResponsible for Agonism of Pergolide at Serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A Receptors

Tilo Görnemann, Harald Hübner,Peter Gmeiner, Reinhard Horowski,Klaus Peter Latté, Miroslav Flieger, andHeinz H. Pertz

1136

Doxycycline Attenuates Isoproterenol- and Transverse AorticBanding-Induced Cardiac Hypertrophy in Mice

Mounir Errami, Cristi L. Galindo,Amina T. Tassa, John M. DiMaio,Joseph A. Hill, and Harold R. Garner

1196

Mechanism-Based Pharmacodynamic Modeling ofS(�)-Atenolol: Estimation of in Vivo Affinity for the �1-Adrenoceptor with an Agonist-Antagonist Interaction Model

Tamara J. van Steeg, Jan Freijer,Meindert Danhof, andElizabeth C. M. de Lange

1234

CELLULAR AND MOLECULAR7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(naphthalen-2-ylmethyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (Bz-423), a Benzodiazepine, Suppresses Keratinocyte Proliferationand Has Antipsoriatic Activity in the Human Skin-Severe,Combined Immunodeficient Mouse Transplant Model

Narasimharao Bhagavathula,Kamalakar C. Nerusu, Andrew Hanosh,Muhammad N. Aslam, Thomas B. Sundberg,Anthony W. Opipari, Jr., Kent Johnson,Sewon Kang, Gary D. Glick, andJames Varani

938

Inhibition of the Cardiac L-Type Calcium Channel Currentby Antidepressant Drugs

Ivan Zahradnı́k, Igor Minarovič, andAlexandra Zahradnı́ková

977

Inhibition of Geranylgeranyl Diphosphate Synthase InducesApoptosis through Multiple Mechanisms and DisplaysSynergy with Inhibition of Other Isoprenoid BiosyntheticEnzymes

Amel Dudakovic, Andrew J. Wiemer,Kimberly M. Lamb, Laura A. Vonnahme,Sara E. Dietz, and Raymond J. Hohl

1028

The Journal of

PHARMACOLOGYAnd Experimental Therapeutics

A Publication of the American Society for Pharmacology and Experimental Therapeutics

March 2008 Vol. 324, No. 3

Contents

The Journal of Pharmacology and Experimental Therapeutics (ISSN0022-3565) is published monthly by the American Society for Pharma-cology and Experimental Therapeutics, 9650 Rockville Pike,Bethesda, MD 20814-3995; email: info@aspet.org; web site:www.aspet.org. Periodicals postage paid at Bethesda, MD, and at addi-tional mailing offices. POSTMASTER: Send address changes to The Jour-nal of Pharmacology and Experimental Therapeutics, 9650 RockvillePike, Bethesda, MD 20814-3995. Subscription rates: U.S.: $893.00 forinstitutions and $389.00 for non-ASPET members. Outside the U.S.:$1,049.00 for institutions and $545.00 for non-ASPET members.

Single copy: $79.00. GST Tax Number for Canadian subscribers: BN:13489 2330 RT. Indexed or abstracted by Biochemistry & BiophysicsCitation Index®, Biological Abstracts, BIOSIS Previews Database, Bio-Sciences Information Services, Current Awareness in Biological Sci-ences, Current Contents®/Life Sciences, EMBASE/Excerpta Medica,Index Medicus, Medical Documentation Service®, PsycINFO, Refer-ence Update®, Research Alert®, Science Citation Index®, SciSearch®,and SIIC Data Bases. Copyright © 2008 by the American Society forPharmacology and Experimental Therapeutics. All rights reserved.Printed in the U.S.A.

Involvement of P2Y1 and P2Y11 Purinoceptors inParasympathetic Inhibition of Colonic Smooth Muscle

Brian F. King andAndrea Townsend-Nicholson

1055

A Conservative, Single-Amino Acid Substitution in the SecondCytoplasmic Domain of the Human Serotonin2C ReceptorAlters Both Ligand-Dependent and -Independent ReceptorSignaling

Kelly A. Berg, John Dunlop,Teresa Sanchez, Michelle Silva, andWilliam P. Clarke

1084

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle andInducing Apoptosis via Rac1/c-Jun NH2-Terminal KinaseActivation in Human Melanoma Cells

Marı́a J. Muñoz-Alonso,Laura González-Santiago, Natasha Zarich,Teresa Martı́nez, Enrique Alvarez,José Marı́a Rojas, and Alberto Muñoz

1093

Statins Decrease Expression of the ProinflammatoryNeuropeptides Calcitonin Gene-Related Peptide and SubstanceP in Sensory Neurons

Robert C. Bucelli, Eugene A. Gonsiorek,Woo-Yang Kim, Donald Bruun,Richard A. Rabin, Dennis Higgins, andPamela J. Lein

1172

Estrogen Receptor-Independent Neuroprotection via ProteinPhosphatase Preservation and Attenuation of PersistentExtracellular Signal-Regulated Kinase 1/2 Activation

Kun Don Yi, Zu Yun Cai,Douglas F. Covey, and James W. Simpkins

1188

Erythropoietin Stimulates Cancer Cell Migration andActivates RhoA Protein through a Mitogen-Activated ProteinKinase/Extracellular Signal-Regulated Kinase-DependentMechanism

Sumaya N. Hamadmad andRaymond J. Hohl

1227

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPYThe Effects of Cyclooxygenase-2 Expression in ProstateCancer Cells: Modulation of Response to Cytotoxic Agents

Ayaz Mehar, Patricia Macanas-Pirard,Atsushi Mizokami, Yutaka Takahashi,Georges E. N. Kass, and Helen M. Coley

1181

ENDOCRINE AND DIABETESStudies with an Orally Bioavailable �V Integrin Antagonist inAnimal Models of Ocular Vasculopathy: RetinalNeovascularization in Mice and Retinal Vascular Permeabilityin Diabetic Rats

Rosemary J. Santulli, William A. Kinney,Shyamali Ghosh, Bart L. DeCorte, Li Liu,Robert W. A. Tuman, Zhao Zhou,Norman Huebert, Sven E. Bursell,Alan C. Clermont, Maria B. Grant,Lynn C. Shaw, Shaker A. Mousa,Robert A. Galemmo, Jr., Dana L. Johnson,Bruce E. Maryanoff, and Bruce P. Damiano

894

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENALCellular Targeting of the Apoptosis-Inducing CompoundGliotoxin to Fibrotic Rat Livers

W. I. Hagens, L. Beljaars, D.A. Mann,M. C. Wright, B. Julien, S. Lotersztajn,C. Reker-Smit, and K. Poelstra

902

INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMAReduction of Peroxisome Proliferation-Activated Receptor �Expression by �-Irradiation as a Mechanism Contributing toInflammatory Response in Rat Colon: Modulation by the 5-Aminosalicylic Acid Agonist

Christine Linard, Olivier Grémy, andMarc Benderitter

911

p38�-Selective Mitogen-Activated Protein Kinase InhibitorSD-282 Reduces Inflammation in a Subchronic Model ofTobacco Smoke-Induced Airway Inflammation

Satyanarayana Medicherla,Mary F. Fitzgerald, Dianne Spicer,Paul Woodman, Jing Y. Ma,Ann M. Kapoun, Sarvajit Chakravarty,Sundeep Dugar, Andrew A. Protter, andLinda S. Higgins

921

Thionamides Inhibit the Transcription Factor Nuclear Factor-�B by Suppression of Rac1 and Inhibitor of �B Kinase �

Matjaz Humar, Hannah Dohrmann,Philipp Stein, Nikolaos Andriopoulos,Ulrich Goebel, Martin Roesslein,Rene Schmidt, Christian I. Schwer,Torsten Loop, Klaus K. Geiger,Heike L. Pahl, and Benedikt H.J. Pannen

1037

METABOLISM, TRANSPORT, AND PHARMACOGENOMICSInhibitor Binding in the Human Renal Low- and High-Affinity Na�/Glucose Cotransporters

Ana M. Pajor, Kathleen M. Randolph,Sandy A. Kerner, and Chari D. Smith

985

Selegiline Is a Mechanism-Based Inactivator of CYP2A6Inhibiting Nicotine Metabolism in Humans and Mice

Eric C.K. Siu and Rachel F. Tyndale 992

Identification and Design of Peptides as a New Drug DeliverySystem for the Brain

Michel Demeule, Anthony Régina,Christian Ché, Julie Poirier, Tran Nguyen,Reinhard Gabathuler, Jean-Paul Castaigne,and Richard Béliveau

1064

Age-Dependent Kinetics and Metabolism of Dichloroacetate:Possible Relevance to Toxicity

Albert L. Shroads, Xu Guo, Vaishali Dixit,Hui-Ping Liu, Margaret O. James, andPeter W. Stacpoole

1163

Extracting Global System Dynamics of CorticosteroidGenomic Effects in Rat Liver

E. Yang, R. R. Almon, D. C. DuBois,W. J. Jusko, and I. P. Androulakis

1243

NEUROPHARMACOLOGY□S Trace Amine-Associated Receptor 1 Modulates Dopaminergic

ActivityLothar Lindemann, Claas Aiko Meyer,Karine Jeanneau, Amyaouch Bradaia,Laurence Ozmen, Horst Bluethmann,Bernhard Bettler, Joseph G. Wettstein,Edilio Borroni, Jean-Luc Moreau, andMarius C. Hoener

948

□S In Vivo �-Secretase 1 Inhibition Leads to Brain A� Loweringand Increased �-Secretase Processing of Amyloid PrecursorProtein without Effect on Neuregulin-1

Sethu Sankaranarayanan, Eric A. Price,Guoxin Wu, Ming-Chih Crouthamel,Xiao-Ping Shi, Katherine Tugusheva,Keala X. Tyler, Jason Kahana,Joan Ellis, Lixia Jin, Thomas Steele,Shawn Stachel, Craig Coburn, andAdam J. Simon

957

Increased C-Fiber Nociceptive Input Potentiates InhibitoryGlycinergic Transmission in the Spinal Dorsal Horn

Hong-Yi Zhou, Hong-Mei Zhang,Shao-Rui Chen, and Hui-Lin Pan

1000

Arginine 246 of the Pretransmembrane Domain 1 RegionAlters 2,2,2-Trichloroethanol Action in the 5-Hydroxytryptamine3A Receptor

Xiang-Qun Hu and Robert W. Peoples 1011

2-Methoxymethyl-Salvinorin B Is a Potent � Opioid ReceptorAgonist with Longer Lasting Action in Vivo Than SalvinorinA

Yulin Wang, Yong Chen, Wei Xu,David Y.W. Lee, Zhongze Ma,Scott M. Rawls, Alan Cowan, andLee-Yuan Liu-Chen

1073

The Triple Uptake Inhibitor (1R,5S)-(�)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0] Hexane Hydrochloride(DOV 21947) Reduces Body Weight and Plasma Triglyceridesin Rodent Models of Diet-Induced Obesity

Joseph P. Tizzano, D. Sloan Stribling,Diego Perez-Tilve, Alison Strack,Andrea Frassetto, Richard Z. Chen,Tung M. Fong, Lauren Shearman,Philip A. Krieter, Matthias H. Tschöp,Phil Skolnick, and Anthony S. Basile

1111

Isoflurane Is a Potent Modulator of Extrasynaptic GABAAReceptors in the Thalamus

Fan Jia, Minerva Yue, Dev Chandra,Gregg E. Homanics, Peter A. Goldstein, andNeil L. Harrison

1127

A Selective Nav1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide],Attenuates Spinal Neuronal Activity in Neuropathic Rats

Steve McGaraughty, Katharine L. Chu,Marc J. C. Scanio, Michael E. Kort,Connie R. Faltynek, and Michael F. Jarvis

1204

S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), aPreferential Dopamine D3 versus D2 Receptor Antagonist andPotential Antipsychotic Agent: III. Actions in Models ofTherapeutic Activity and Induction of Side Effects

Mark J. Millan, Florence Loiseau,Anne Dekeyne, Alain Gobert, Gunnar Flik,Thomas I. Cremers, Jean-Michel Rivet,Dorothée Sicard, Rodolphe Billiras, andMauricette Brocco

1212

TOXICOLOGYInhibition of Mitochondrial Hydrogen Peroxide Production byLipophilic Metalloporphyrins

Pablo R. Castello, Derek A. Drechsel,Brian J. Day, and Manisha Patel

970

Omeprazole Stimulates the Induction of Human Insulin-LikeGrowth Factor Binding Protein-1 through Aryl HydrocarbonReceptor Activation

Iain A. Murray and Gary H. Perdew 1102

The Butyrylcholinesterase Knockout Mouse as a Model forHuman Butyrylcholinesterase Deficiency

Bin Li, Ellen G. Duysen, Michaela Carlson,and Oksana Lockridge

1146

Succinate Ameliorates Energy Deficits and PreventsDysfunction of Complex I in Injured Renal Proximal TubularCells

Grażyna Nowak, Ginger L. Clifton, andDiana Bakajsova

1155

□S Supplemental material is available online at http://jpet.aspetjournals.org.

About the cover: The Trace amine-associated receptor 1 (TAAR1) is expressed in multiple areas of themouse brain, including the ventral tegmental area. Dopaminergic neurons in this region show anincreased firing frequency in TAAR1 knockout compared to wild-type mice. See the article by Lindemannet al. on page 948 of this issue.

Rick G. Schnellmann, EditorCraig C. Beeson, Assistant Editor

ASSOCIATE EDITORSDarrell R. AbernethyIan AdcockJerry J. BuccafuscoPhilip S. BurtonDavid B. BylundPaul Ernsberger

Mitchell P. FinkAlan R. GintzlerRonald N. HinesMyron K. JacobsonMichael F. Jarvis

Norbert E. KaminskiRaouf A. KhalilDaniel R. KnappLawrence H. LashRoberto Levi

Louis M. LuttrellDavid S. MillerRichard A. MorrisettA. Leslie MorrowMichael J. O’Neill

Bryan L. RothRobert A. RothRoland SeifertKenneth D. TewStephanie W. WattsAlice M. Young

EDITORIAL ADVISORY BOARDGeoffrey W. AbbottThomas J. AbbruscatoPeter AbelEdson X. AlbuquerqueThomas M. ArgentieriBork BalkanLeslie R. BallouWilliam A. BanksJack BergmanDaniel C. BertrandItalo BiaggioniC. Paul BianchiFloyd E. BloomJean-Marie BoeynaemsFranco BorsiniMarco BrottoNancy BrownJohn CharpieLucio G. CostaBrian M. CoxBryan F. CoxBruce N. CronsteinBrian CummingsM. Imad DamajWilliam C. deGroatRussell Delude

Patrick DoughertyFrederick J. EhlertJohn L. EvendenSteven J. FeinmarkGiora Z. FeuersteinStephen F. FlaimAnthony W. FoxCharles P. FranceAlan FrazerGert FrickerRyan FryerBernard W. FutscherJames J. GalliganVadivel GanapathyPatricia E. GaneyRichard A. GillisGary GintantJohn R. GlowaMurali GopalakrishnanSteven M. GrasslGarrett J. GrossPerry V. HalushkaGyorgy HaskoJ. Paul HiebleK. Roger HornbrookSusanna HouraniLeonard L. Howell

Dale G. HoytJohn ImigHarry IschiropoulosEdwin K. JacksonKenneth M. JohnsonWilliam J. JuskoPeter W. KalivasLaurence S. KaminskyJonathan L. KatzMark R. KelleyLewis B. KinterThomas KocarekGeorge F. KoobSuk-Hee LeeBenedict R. LucchesiJoseph J. LynchRosalinde MasereeuwPhilip R. MayeuxDonald E. McMillanMark J. MillanGary W. MillerHitoshi MorikawaHasan MukhtarL. Charles MurrinMichael NaderStanley NattelS. Stevens Negus III

Kim A. NeveYasuyuki NomuraJames S. NorrisGrazyna NowakJames M. O’DonnellPatricio O’DonnellMichael F. O’NeillMark OsinskiK. Sandy PangAchilles J. PappanoB. Kevin ParkSandra PfisterMichael T. PiascikRussell O. PieperJoseph W. PolliJohn B. PritchardRussell A. ProughRaymond M. QuockJ. Larry RenfroMichael C. SanguinettiJonathan G. ScammellMichal Laniado

SchwartzmanFederico SestiDavid R. SibleyTheodore A. SlotkinMark Smith

Philip C. SmithQuentin R. SmithNikolai M. SoldatovEdward E. SoltisPatricia K. SonsallaMichael D. SouthallRoger D. SpealmanFrancis G. SpinaleJohn L. SutkoDouglas SweetIstvan SzelenyiMilt TeitlerPaul F. TerranovaAlvin V. TerryMyron L. ToewsGeorge J. TrachteHiroshi UedaMichael R. VaskoSandra P. WelchDaniel WierdaMichael WilliamsRaymond J. WinquistJeffrey M. WitkinBryan K. Yamamoto

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The Journal of Pharmacology and Experimental TherapeuticsA Publication of the American Society for Pharmacology and Experimental Therapeutics

Founded by John J. Abel - 1908