Endogenous Opioids Contribute to Remote Ischemic Preconditioning-Induced Vascular Protection in Humans

Introduction: Remote Ischemic Preconditioning (RIPC) is a cardio-protective therapy characterized by repeated cycles of limb ischemia and reperfusion. RIPC attenuates cardiac damage during ischemia-reperfusion injury (IRI), and preclinical studies suggest that this phenomenon is mediated through the release of endogenous opioids. We aimed to interrogate the role of endogenous opioids in RIPC-signaling in humans, using an arm model of IRI which consists of measuring reductions in brachial artery flow mediated dilation (FMD; index of vascular function) in response to upper arm ischemia and reperfusion. We hypothesized that a single bout of arm RIPC would attenuate IRI-induced reductions in FMD, and that this attenuation would be prevented by systemic opioid receptor blockade via intranasal naloxone. Methods: 11 healthy adults (8M/3F, age=28±8yr) completed three experimental conditions in which brachial artery FMD was measured pre and post IRI. IRI was induced via 20-min of upper arm ischemia and 20-min of reperfusion via arm cuff inflation to 250mmHg with subsequent arm cuff deflation. During the control condition (CON), 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 cuff deflation (40-min total) prior to the IRI. During the opioid receptor blockade condition (Naloxone), RIPC was performed in the presence of systemic opioid receptor blockade via a single dose of intranasal naloxone (4mg) which was administered during the first 5-min cycle of RIPC. Reductions in FMD from pre-IRI vs post-IRI were compared between conditions via a two-way repeated measures ANOVA (factor 1: time, factor 2, condition ) followed by Tukey post-hoc tests. Results: IRI induced reductions in FMD during the CON condition (Pre=6.1±2.4%, Post=3.5±2.8%, p<0.001) and these reductions were prevented during the RIPC condition (Pre=5.9±2.2%, Post=4.9±2.8%, P=0.15). These protective effects were abolished during the Naloxone condition (Pre=6.6±2.7%, Post=3.5±1.9%, p<0.001), with FMD being reduced to a similar magnitude as was observed during the CON. Conclusions: These findings demonstrate that a single bout of arm RIPC provides vascular protection from IRI in humans through an opioid-dependent mechanism. This work was supported by start-up funds from the University of North Texas This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.