Remote Ischemic Preconditioning Attenuates Ischemia-Reperfusion Injury Induced Reductions in Vascular Function through Release of Endogenous Opioids

Remote Ischemic Preconditioning (RIPC) is a therapy characterized by repeated bouts of limb ischemia and reperfusion. RIPC protects against ischemia-reperfusion injury (IRI), and preclinical studies suggest that this is mediated through release of endogenous opioids. We aimed to interrogate the role of endogenous opioids in RIPC-signaling in humans, using an arm model of IRI. We hypothesized that RIPC would attenuate IRI-induced reductions in brachial artery flow mediated dilation (FMD), and that this would be prevented by systemic opioid receptor blockade. 11 healthy adults (8M/3F, age=28±8y) completed three experimental visits in which IRI was induced via 20-min upper arm ischemia and 20-min reperfusion achieved via upper arm cuff inflation to 250mmHg. FMD was measured at rest and again following IRI. During the control condition, RIPC was not performed. During the RIPC condition, RIPC was performed on the contralateral arm via 4 cycles of 5-min cuff inflation (250mmHg) with 5-min reperfusion. During the opioid receptor blockade condition (Naloxone), RIPC was performed in the presence of systemic opioid receptor blockade via intranasal naloxone (4mg) which was administered during the first 5-min cycle of RIPC. The change in FMD from baseline vs post-IRI were compared between visits via a two-way repeated measures ANOVA (factor 1: time, factor 2, condition) followed by Tukey post-hoc tests. IRI reduced FMD during the Control (Pre=6.1±2.4%, Post=3.5±2.8%, P<0.001) and Naloxone (Pre=6.6±2.7%, Post=3.5±1.9%, P<0.001) conditions but not during the RIPC condition (Pre=5.9±2.2%, Post=4.9±2.8%, P=0.14). These findings demonstrate that RIPC provides vascular protection from IRI in humans through an opioid-dependent mechanism.