Pharmacological preconditioning with opioids for myocardial protection.

摘要

The objective of this research was to investigate the role of opioids in myocardial protection of the large mammalian swine heart. The isolated working heart model of swine was carefully characterized by comparing increasing doses of a known cardiac depressant, halothane, in vivo and in vitro. The results of this first investigation displayed a reduced, but reproducible, in vitro function which was slightly depressed, most likely due to post-ischemic effects and lack of neurohumoral inputs (denervation, no circulating catecholamines). Subsequently, the effects of in vivo administration of δ-receptor specific opioid [D-Ala2, D-Leu5]-Enkephalin (DADLE), and morphine on post-ischemic function, energy metabolism (high energy phosphates, lactate efflux) and myocardial damage were studied in isolated working swine hearts after 75 minutes of 4°C ischemia. DADLE and morphine preconditioned hearts elicited better myocardial function at 75 minutes of reperfusion compared to untreated controls. These changes were associated with lower lactate effluxes, but not better preserved high energy phosphate levels or reduced myocardial damage.; An acute coronary occlusion model using pentobarbital anesthetized swine was developed to investigate the effects of opioid preconditioning on: (1) infarct size, (2) regional and global myocardial function, and (3) arrhythmias. Prior to a 45 minute occlusion and 180 minute reperfusion of the left anterior descending coronary artery groups received either: (1) Saline (controls); (2) DADLE; (3) [D-pen2,5]-Enkephalin (DPDPE); (4) Deltorphin D; or (5) ischemic preconditioning (IP). DPDPE and Deltorphin D pretreatment significantly reduced infarct size (p 0.01), while DADLE had not effect. No differences in global or regional myocardial function or arrhythmia scores were observed between groups. A pro-fibrillatory effect of IP was observed (p 0.01). These studies are the first to report the role of δ-receptor specific opioid agonists in myocardial protection in large mammalian hearts and, in particular, within the swine species.