Remote ischemic preconditioning attenuates ischemia-reperfusion injury-induced reductions in vascular function through release of endogenous opioids

Abstract

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 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. 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. Eleven healthy adults (8 M/3 F, age = 28 ± 8 yr) 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 250 mmHg. 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 four cycles of 5-min cuff inflation (250 mmHg) 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 (4 mg), which was administered during the first 5-min cycle of RIPC. The change in FMD from baseline versus post-IRI was 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.NEW & NOTEWORTHY Remote ischemic preconditioning (RIPC) is a cardioprotective therapy characterized by brief cycles of limb ischemia and reperfusion. We demonstrate that a single bout of arm RIPC provides protection from ischemia-reperfusion injury-induced reductions in vascular function in healthy adults. This protection was attenuated when RIPC was administered in the presence of systemic opioid-receptor blockade via intranasal naloxone. These findings suggest that endogenous opioids contribute to RIPC-induced protection of vascular function in humans.

Keywords: cardioprotection; enkephalins; flow-mediated dilation; ischemia-reperfusion injury; naloxone.