Activation of Peripheral Delta Opioid Receptors Increases Cardiac Tolerance to Arrhythmogenic Effect of Ischemia/Reperfusion

ObjectivesThe objective of this study was to investigate the role of peripheral , (1), (2), and nociceptin opioid receptors agonists in the regulation of cardiac tolerance to the arrhythmogenic effect of ischemia/reperfusion in rats. MethodsAnesthetized open-chest male Wistar rats were subjected to either 45minutes of left coronary artery occlusion (phase 1a 10minutes and phase 2b 35minutes) and 2hours of reperfusion in Experiment 1 or 10minutes of ischemia and 10minutes of reperfusion in Experiment 2. In Experiment 1, saline or vehicle controls and the mu-specific opioids dermorphin-H (Derm-H) and ([d-Ala2, N-Me-Phe4, Gly-ol5] enkephalin (DAMAGO); the delta-1-specific opioid d-Pen2,5enkephalin (DPDPE); nociceptin; and the delta-2-specific opioids deltorphin-II (Delt-II), Delt-Dvariant (Delt-Dvar), and deltorphin-E (Delt-E) were infused 15minutes prior to ischemia. In Experiment 2, DPDPE, Delt-D, Delt-Dvar, and Delt-E were infused at 15minutes prior to ischemia. The universal opioid receptor antagonist naltrexone, the peripherally acting antagonist naloxone methiodide, the selective (1) antagonist 7-benzylidene naltrexone maleate, and the specific (2) antagonist naltriben mesylate were infused 25minutes prior to ischemia. ResultsIn Experiment 1, pretreatment with the opioids Derm-H and DAMGO, DPDPE, and nociceptin at all doses tested did not reduce the incidence of ischemia-induced arrhythmias compared to controls during 45minutes of ischemia. The (2) opioids Delt-II (0.12mg/kg), Delt-Dvar (0.3mg/kg), and Delt-E (0.18mg/kg) all demonstrated significant antiarrhythmic effects at the 150nmol/kg dose compared to saline or vehicle controls. Nine of 19 animals treated with Delt-II were tolerant without ventricular arrhythmias to the arrhythmogenic effect of ischemia during the first 10minutes of ischemia (phase 1a) and 11 of 19 were without ventricular arrhythmias during the following 35minutes of ischemia (phase 1b). Delt-II also decreased the incidence of premature ventricular contractions and ventricular tachycardia by almost half during phase 1a. Delt-II did not affect the incidence of ventricular fibrillation (VF). Pretreatment with Delt-Dvar and Delt-E completely blocked the incidence of VF in phase 1b. Delt-E also decreased premature ventricular contractions by 50%, and the incidence of ventricular tachycardia decreased over twofold in phase 1b of ischemia. There was no enhanced tolerance by any of the delta-2 opioids to the arrhythmogenic effect of reperfusion after long-term ischemia. In Experiment 2, after 10minutes of ischemia and 10minutes of reperfusion, Delt-II (0.12mg/kg) reduced the incidence of premature ventricular contractions and ventricular tachycardia compared to controls, and completely blocked the incidence of VF following 10minutes of reperfusion. Delt-Dvar and Delt-E were without effect, as was DPDPE following 10minutes of reperfusion. The antiarrhythmic effect of Delt-II during 10minutes of ischemia and 10minutes of reperfusion was completely blocked by the peripherally acting opioid receptor inhibitor naloxone methiodide and the selective delta-2 opioid receptor inhibitor naltriben mesylate, but not by the selective delta-1 inhibitor 7-benzylidene naltrexone maleate. The antagonists alone had no effect on arrhythmogenesis. ConclusionsPeripheral delta-2 opioid receptor activation by Delt-II, Delt-Dvar, and Delt-E enhanced cardiac tolerance to the arrhythmogenic effects of ischemia. (C) 2013 by the Society for Academic Emergency Medicine Resumen ObjetivosEl objetivo de este estudio fue investigar el papel de los receptores agonistas opiaceos perifericos , (1), (2) y nociceptina en la regulacion de la tolerancia cardiaca al efecto arritmogenico de la isquemia-reperfusion en las ratas. MetodologiaRatas Wistar machos anestesiadas para la apertura del torax fueron sometidas a: 1) experimento 1: 45 minutos de oclusion de la arteria coronaria izquierda (fase 1a 10min y fase 2b 35min), y 2 horas de reperfusion; o 2) experimento 2: 10 minutos de isquemia y 10 minutos de reperfusion. En el Experimento 1, 15 minutos antes de la isquemia, se perfundio suero salino o medio de los controles y los opioides especificos Dermorfina-H (Derm-H), y ([D-Ala2, N-Me-Phe4, Gly-ol5] encefalina (DAMAGO); el opiode especifico (1) D-Pen2,5encefalina (DPDPE); nociceptina; y los opioides especificos (2) Deltorfina-II (Delt-II), Delt-varianteD (Delt-Dvar), y Deltorfina-E (Delt-E). En el Experimento 2, 15 minutos antes de la isquemia, se perfundio DPDPE, Delt-D, Delt-Dvar, y Delt-E. Se perfudieron, 25 minutos antes de la isquemia, el antagonista del receptor opiaceo universal (naltrexona), naloxona metiodida (antagonista que actua a nivel periferico), el antagonista selectivo (1) 7-benzilideno naltrexona maleato y el antagonista especifico (2) naltriben mesilato. ResultadosEn el Experimento 1, el tratamiento previo con los opioides Derm-H y DAMGO, DPDPE, asi como nociceptina a cualquier dosis probada, no redujo la incidencia de arritmias inducidas por isquemia en comparacion con los controles durante 45 minutos de isquemia. Los opioides (2) Delt-II (0,12mg/kg), Delt-Dvar (0,3mg/kg) y Delt-E (0,18mg/kg) demostraron todos efectos antiarritmicos significativos a la dosis de 150nmol/kg en comparacion con salino o medio de los controles. Nueve de los 19 animales tratados con Delt-II toleraron sin arritmias ventriculares (SAV) el efecto arritmogenico de la isquemia durante los primeros 10 minutos de isquemia (fase 1a) y 11 de 19 SAV durante los siguientes 35 minutos de isquemia (fase 1b). Delt-II tambien disminuyo la incidencia de contracciones ventriculares prematuras (CVP) y taquicardia ventricular (TV) durante casi la mitad de la fase 1a. Delt-II no afecto a la incidencia de fibrilacion ventricular (FV). El tratamiento previo con Delt-Dvar y Delt-E bloqueo completamente la incidencia de FV en la fase 1b. Delt-E tambien disminuyo las CVP un 50%, y la incidencia de TV se redujo mas del doble en la fase 1b de isquemia. No hubo mayor tolerancia por ninguno de los opioides (2) para el impacto arritmogenico de la reperfusion tras el largo tiempo de isquemia. En el Experimento 2, tras 10 minutos de isquemia y 10 minutos de reperfusion, Delt-II (0,12mg/kg) redujo la incidencia de CVP y TV comparado con los controles, y bloqueo completamente la incidencia de FV a los 10 minutos de la reperfusion. Delt-Dvar y Delt-E no tuvieron efecto, como lo tuvo DPDPE a los 10 minutos de la reperfusion. El efecto antiarritmico de Delt-II durante los 10 minutos de isquemia y 10 minutos de reperfusion fue completamente bloqueado por el inhibidor del receptor opiaceo de accion periferica naloxona metiodida y el inhibidor del receptor opiaceo delta-2 selectivo naltriben mesilato, pero no por el inhibidor (1) selectivo 7-benzylidene naltrexona maleato. Los antagonistas aislados no tienen efectos en la arritmogenesis. ConclusionesLa activacion del receptor opiaceo (2) periferico por Delt-II, Delt-Dvar y Delt-E aumento la tolerancia cardiaca al impacto arritmogenico de la isquemia.