Abstract P109: Role of Endogenous Opioids in Remote Ischemic Preconditioning in Humans
Background: Ischemic preconditioning (IPC) reduces tissue damage caused by ischemia-reperfusion (IR) injury. Protection from IR injury can also be achieved by brief periods of ischemia applied at a remote site before the injurious ischaemic event (remote IPC; RIPC). However, the precise mechanisms via which the protective signal is transferred to remote sites remain elusive. Animal studies have implicated endogenous opioids as humoral mediators of systemic protection by RIPC, but the role of opioids in RIPC in humans has not been characterised. We hypothesised that opioid receptor blockade would abolish the protection afforded by RIPC against IR injury in humans in vivo.
Methods: Endothelial function was assessed by flow-mediated dilation (FMD) before and after IR (20 minutes of arm ischemia followed by reperfusion) in ten healthy volunteers. RIPC was induced by 3 cycles of 5 minute ischemia and reperfusion applied on the contralateral arm immediately before IR. To determine the dependence of RIPC on endogenous opioids, the non-selective opioid receptor blocker naloxone was administered intravenously (6mg loading dose and 0.1mg/min for 30 minutes) during the application of the RIPC stimulus. To exclude any direct effects of naloxone on the endothelial response to IR, FMD was measured before and after IR in the presence of systemic naloxone. FMD (percentage change from baseline diameter) was expressed as mean±SEM and compared by ANOVA (n=9).
Results: IR alone caused a significant reduction in FMD after 20 minutes of reperfusion (7.8±0.8% pre-IR; 3.6±0.7% post-IR, p<0.01). This reduction was prevented by RIPC (7.2±0.5% pre-IR; 6.9±1.0% post-IR, NS). Systemic naloxone blocked the protective effects of RIPC (7.0±0.6% pre-IR; 2.8±0.6% post-IR, p<0.001) but had no direct effect on the endothelial response to IR.
Conclusions: These data indicate, for the first time in humans, that endogenous opioids are involved in the systemic protection by RIPC. This could be explained by activation of neuro-hormonal reflex by endogenous opioids. It remains to be determined whether a circulating opioid mediates the systemic spread of protection of RIPC.