zpt0040800SPC1.qxd 3/11/08 10:55 AM Page 1 Volume 325 ■ Number 1 ■ April 2008 ■ ISSN 0022-3565 The Journal of PHARMACOLOGY And Experimental Therapeutics A Adaptations (Network Architecture) Can Create Unpredicted Therapeutic Actions Drug Predicted Effect Unexpected Effect B Complexity Creates Unpredicted Targets Predicted Effect Drug Target Unpredicted Target A Publication of the American Society for Pharmacology and Experimental Therapeutics Edited for the Society by Rick G. Schnellmann The Journal of PHARMACOLOGY And Experimental Therapeutics A Publication of the American Society for Pharmacology and Experimental Therapeutics April 2008 Vol. 325, No. 1 Contents PERSPECTIVES IN PHARMACOLOGY Exploiting Complexity and the Robustness of Network Marc K. Hellerstein 1 Architecture for Drug Discovery BEHAVIORAL PHARMACOLOGY Early Postnatal Stress Alters Place Conditioning to Both ␮- and Clifford C. Michaels and Stephen G. Holtzman 313 ␬-Opioid Agonists CARDIOVASCULAR □ ␤ S Design of Mutant 2 Subunits as Decoy Molecules to Reduce the Sabine Te´le´maque, Swapnil Sonkusare, 37 ,Expression of Functional Ca2؉ Channels in Cardiac Cells Terrie Grain, Sung W. Rhee, Joseph R. Stimers Nancy J. Rusch, and James D. Marsh Sphingosine 1-Phosphate Inhibits Nitric Oxide Production Takuji Machida, Yukihiro Hamaya, 200 Induced by Interleukin-1␤ in Rat Vascular Smooth Muscle Cells Sachiko Izumi, Yumika Hamaya, Kenji Iizuka, Yasuyuki Igarashi, Masaru Minami, Roberto Levi, and Masahiko Hirafuji Andrographolide Up-Regulates Cellular-Reduced Glutathione Anthony Y. H. Woo, Mary M. Y. Waye, 226 Level and Protects Cardiomyocytes against Stephen K. W. Tsui, Sandy T. W. Yeung, and Hypoxia/Reoxygenation Injury Christopher H. K. Cheng Orally Available Levosimendan Dose-Related Positive Inotropic Satoshi Masutani, Heng-Jie Cheng, 236 and Lusitropic Effect in Conscious Chronically Instrumented Minja Hyttila¨-Hopponen, Jouko Levijoki, Normal and Heart Failure Dogs Aira Heikkila¨, Arja Vuorela, William C. Little, and Che-Ping Cheng Evoked Changes in Cardiovascular Function in Rats by Infusion of Jason A. Segreti, Kennan C. Marsh, 331 Levosimendan, OR-1896 [(R)-N-(4-(4-Methyl-6-oxo-1,4,5,6- James S. Polakowski, and Ryan M. Fryer tetrahydropyridazin-3-yl)phenyl)acetamide], OR-1855 [(R)-6-(4- Aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one], Dobutamine, and Milrinone: Comparative Effects on Peripheral Resistance, Cardiac Output, dP/dt, Pulse Rate, and Blood Pressure CELLULAR AND MOLECULAR Activation and Inhibition of Adenylyl Cyclase Isoforms by Cibele Pinto, Dan Papa, Melanie Hu¨bner, 27 Forskolin Analogs Tung-Chung Mou, Gerald H. Lushington, and Roland Seifert Phosphorylation Increases Affinity of the Phosphodiesterase-5 Emmanuel P. Bessay, Mitsi A. Blount, 62 Catalytic Site for Tadalafil Roya Zoraghi, Alfreda Beasley, Kennard A. Grimes, Sharron H. Francis, and Jackie D. Corbin Proteasome-Dependent Pharmacological Rescue of Cystic Fibrosis Caroline Norez, Fre´de´ric Bilan, Alain Kitzis, 89 Transmembrane Conductance Regulator Revealed by Mutation of Yvette Mettey, and Fre´de´ric Becq Glycine 622 The Journal of Pharmacology and Experimental Therapeutics (ISSN Single copy: $79.00. GST Tax Number for Canadian subscribers: BN: 0022-3565) is published monthly by the American Society for Pharma- 13489 2330 RT. Indexed or abstracted by Biochemistry & Biophysics cology and Experimental Therapeutics, 9650 Rockville Pike, Citation Index®, Biological Abstracts, BIOSIS Previews Database, Bio- Bethesda, MD 20814-3995; email: [email protected]; web site: Sciences Information Services, Current Awareness in Biological Sci- www.aspet.org. Periodicals postage paid at Bethesda, MD, and at addi- ences, Current Contents®/Life Sciences, EMBASE/Excerpta Medica, tional mailing offices. POSTMASTER: Send address changes to The Jour- Index Medicus, Medical Documentation Service®, PsycINFO, Refer- nal of Pharmacology and Experimental Therapeutics, 9650 Rockville ence Update®, Research Alert®, Science Citation Index®, SciSearch®, Pike, Bethesda, MD 20814-3995. Subscription rates: U.S.: $893.00 for and SIIC Data Bases. Copyright © 2008 by the American Society for institutions and $389.00 for non-ASPET members. Outside the U.S.: Pharmacology and Experimental Therapeutics. All rights reserved. $1,049.00 for institutions and $545.00 for non-ASPET members. Printed in the U.S.A. Paradoxical Behavior of Neuromedin U in Isolated Smooth Paul J. Brighton, Alan Wise, Narinder B. Dass, 154 Muscle Cells and Intact Tissue and Gary B. Willars G Protein Coupling and Ligand Selectivity of the D2L and D3 J. Robert Lane, Ben Powney, Alan Wise, 319 Dopamine Receptors Stephen Rees, and Graeme Milligan Mapping the Structural Requirements in the CB1 Cannabinoid Ankur Kapur, Patrick Samaniego, 341 Receptor Transmembrane Helix II for Signal Transduction Ganesh A. Thakur, Alexandros Makriyannis, and Mary E. Abood CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY Design and Evaluation of S-Nitrosylated Human Serum Albumin Naohisa Katayama, Keisuke Nakajou, 69 as a Novel Anticancer Drug Hisakazu Komori, Kunitoshi Uchida, Jun-ichi Yokoe, Norikiyo Yasui, Hisashi Yamamoto, Toshiya Kai, Makoto Sato, Takenobu Nakagawa, Motohiro Takeya, Toru Maruyama, and Masaki Otagiri ENDOCRINE AND DIABETES □S (R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl- Leo Thomas, Matthias Eckhardt, 175 quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a Elke Langkopf, Moh Tadayyon, Novel Xanthine-Based Dipeptidyl Peptidase 4 Inhibitor, Has a Frank Himmelsbach, and Michael Mark Superior Potency and Longer Duration of Action Compared with Other Dipeptidyl Peptidase-4 Inhibitors GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL □S Discovery and Characterization of Novel Tryptophan Hydroxylase Qingyun Liu, Qi Yang, Weimei Sun, 47 Inhibitors That Selectively Inhibit Serotonin Synthesis in the Pete Vogel, William Heydorn, Xiang-Qing Yu, Gastrointestinal Tract Zhixiang Hu, Wangsheng Yu, Brandie Jonas, Randy Pineda, Valerie Calderon-Gay, Michael Germann, Emily O’Neill, Robert Brommage, Emily Cullinan, Ken Platt, Alan Wilson, Dave Powell, Arthur Sands, Brian Zambrowicz, and Zhi-cai Shi Pharmacological Properties of N-(3,5-Diamino-6-chloropyrazine-2- Andrew J. Hirsh, Jim Zhang, Andra Zamurs, 77 ,carbonyl)-N؅-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine Jacquelyn Fleegle, William R. Thelin Methanesulfonate (552-02), a Novel Epithelial Sodium Channel Ray A. Caldwell, Juan R. Sabater, Blocker with Potential Clinical Efficacy for Cystic Fibrosis Lung William M. Abraham, Mark Donowitz, Disease Boyoung Cha, Kevin B. Johnson, Judith A. St. George, M. Ross Johnson, and Richard C. Boucher Inhibitory Phosphorylation of Soluble Guanylyl Cyclase by Karnam S. Murthy 183 Muscarinic m2 Receptors via G␤␥-Dependent Activation of c-Src Kinase 5-Amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2- Tadayoshi Mikami, Yasuo Ochi, Keiko Suzuki, 190 methylimidazo[1,2-␣]pyridine-8-carboxamide (CJ-033,466), a Toshiyuki Saito, Yutaka Sugie, and Novel and Selective 5-Hydroxytryptamine4 Receptor Partial Minoru Sakakibara Agonist: Pharmacological Profile in Vitro and Gastroprokinetic Effect in Conscious Dogs Regulation of Renal Ectophosphodiesterase by Protein Kinase C Edwin K. Jackson and Zaichuan Mi 210 and Sodium Diet Rutaecarpine Induces Chloride Secretion across Rat Isolated DaZheng Wu and ZhiBi Hu 256 Distal Colon INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA Anti-Inflammatory and Analgesic Potency of Lei Guo, Caiying Ye, Wenying Chen, Hua Ye, 10 Carboxyamidotriazole, a Tumorostatic Agent Ru Zheng, Juan Li, Huifen Yang, Xiaoli Yu, and Dechang Zhang □S Treatment of Sepsis-Induced Acquired Protein C Deficiency Mark A. Richardson, Akanksha Gupta, 17 Reverses Angiotensin-Converting Enzyme-2 Inhibition and Lee A. O’Brien, David T. Berg, Bruce Gerlitz, Decreases Pulmonary Inflammatory Response Samreen Syed, Ganesh R. Sharma, Martin S. Cramer, Josef G. Heuer, Elizabeth J. Galbreath, and Brian W. Grinnell The Carbon Monoxide-Releasing Molecule Javier Megı´as, Marı´a Isabel Guille´n, 56 Tricarbonyldichlororuthenium(II) Dimer Protects Human Antonio Bru, Francisco Gomar, and Osteoarthritic Chondrocytes and Cartilage from the Catabolic Marı´a Jose´ Alcaraz Actions of Interleukin-1␤ Evidence for the Role of Mitogen-Activated Protein Kinase Tiziana Genovese, Emanuela Esposito, 100 Signaling Pathways in the Development of Spinal Cord Injury Emanuela Mazzon, Carmelo Muia`, Rosanna Di Paola, Rosaria Meli, Placido Bramanti, and Salvatore Cuzzocrea □S Differential High-Affinity Interaction of Dectin-1 with Natural or Elizabeth L. Adams, Peter J. Rice, 115 Synthetic Glucans Is Dependent upon Primary Structure and Is Bridget Graves, Harry E. Ensley, Hai Yu, Influenced by Polymer Chain Length and Side-Chain Branching Gordon D. Brown, Siamon Gordon, Mario A. Monteiro, Erzsebet Papp-Szabo, Douglas W. Lowman, Trevor D. Power, Michael F. Wempe, and David L. Williams Thiopental Protects Human T Lymphocytes from Apoptosis in Martin Roesslein, David Schibilsky, 217 Vitro via the Expression of Heat Shock Protein 70 Laurent Muller, Ulrich Goebel, Christian Schwer, Matjaz Humar, Rene Schmidt, Klaus K. Geiger, Heike L. Pahl, Benedikt H. J. Pannen, and Torsten Loop METABOLISM, TRANSPORT, AND PHARMACOGENOMICS □S Aberrant Splicing Caused by Single Nucleotide Polymorphism Marco H. Hofmann, Julia K. Blievernicht, 284 c.516G>T [Q172H], a Marker of CYP2B6*6, Is Responsible for Kathrin Klein, Tanja Saussele, Decreased Expression and Activity of CYP2B6 in Liver Elke Schaeffeler, Matthias Schwab,