title: An examination of the cardiac actions of PD117,302, a κ-opioid receptor agonist.
abstract: These studies examined the opioid and non-opioid in vivo and in vitro actions of PD117,302 (((±)-trans-N-methyl-N-[2-(l-pyrrolidinyl)-cyclohexyl]benzo[b]thiophene-4-acetamide), a kappa (κ)-opioid receptor agonist. PD117,302 selectively labeled the κ-opioid receptor in guinea pig cerebellar membranes and in mice the ED50 for analgesia was 2.3µmol/kg. A non opioid cardiovascular assessment of PD117,302 showed that it dose-dependently increased left-ventricular peak systolic pressure in rat isolated perfused hearts but reduced heart rate and blood pressure in anaesthetized rats. Over the concentration range 0.3-30µM in vitro, and dose-range 0.25-4µmol/kg in vivo, PD117,302 dose-dependently prolonged the P-R interval, QRS width and Q-T interval of the rat heart ECG. Naloxone (either 1µM or 8µmol/kg) did not antagonize the observed ECG effects of PD117,302. Cardiac electrical stimulation studies in anesthetized rats showed that threshold currents for capture and fibrillation were increased and effective refractory period (ERP) prolonged. In rats subject to coronary artery occlusion PD117,302 reduced arrhythmia incidence. Intracellular cardiac action potential studies qualified the ECG changes produced by PD117,302 such that there was a dose-dependent reduction in the maximum rate of depolarization of phase 0 (dV/dtmax) and prolongation of the action potential duration (APD). In isolated cardiac myocytes PD117,302 dose-dependently (1-100µM) reduced peak Na(+) current and produced a hyperpolarizing shift in the inactivation curve. Transient outward and sustained outward K(+) currents were blocked by PD117,302. Thus, the ECG changes and antiarrhythmic effects observed in vivo result from direct blockade of multiple cardiac ion channels.
authors.affiliation: Department of Global Safety Pharmacology & Toxicology, Janssen Pharmaceuticals LLC, Raritan, NJ 08869, United States. Electronic address: mkpugsley@yahoo.com.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pugsley
authors.affiliation: Department of Physiology, University of Adelaide, Adelaide, SA, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Saint
authors.affiliation: Porsolt SAS, Z.A de Glatigne, 53940 Le-Genest-Saint-Isle, France.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Hayes
authors.affiliation: Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Abraham
authors.affiliation: Department of Anaesthesia, Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Michael J A
authors.initials: MJ
authors.lastname: Walker
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001667:Binding, Competitive; D002304:Cardiac Pacing, Artificial; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D054059:Coronary Occlusion / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D000067268:Isolated Heart Preparation; D008024:Ligands; D008297:Male; D008807:Mice, Inbred BALB C; D009200:Myocardial Contraction / Q000187:drug effects; D010146:Pain / Q000378:metabolism / Q000517:prevention & control; D017288:Pain Threshold / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D008024:Ligands; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011758:Pyrroles; D017473:Receptors, Opioid, kappa; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013876:Thiophenes; C054718:PD 117302
keywords: Action potential; Antiarrhythmic; Cardiac myocyte; Ischemia; Kappa agonist; PD117,302; Potassium channel; Sodium channel