Brief periods of ischaemia activate systemic mechanisms that induce whole-body tolerance to subsequent prolonged and injurious ischaemia. This phenomenon, remote ischaemic preconditioning (RIPC), is sufficiently acute to reduce ischaemia-reperfusion (IR) injury even when applied
simultaneously
with injurious ischaemia. This aspect of RIPC is termed remote postconditioning (RPostC). We have previously demonstrated a role for the autonomic nervous system in RIPC. Using an
in vivo
model of endothelial IR injury, we determined if RPostC is dependent on adrenergic autonomic mechanisms. Vascular ultrasound was used to assess endothelial function in healthy volunteers by measuring dilatation of the brachial artery in response to increased blood flow during reactive hyperaemia (flow-mediated dilatation; FMD). Endothelial IR injury was induced by 20 min of upper limb ischaemia (inflation of a blood pressure cuff to 200 mm Hg) followed by reperfusion. RPostC was induced by applying 2 cycles of 5 minutes ischaemia and 5 minutes reperfusion on the leg during arm ischaemia (via a second blood pressure cuff). In order to determine the dependence of RPostC on autonomic activation, we administered the alpha adrenoceptor blocker phentolamine (0.2– 0.7mg/min, intravenously) during the application of the RPostC stimulus. FMD was determined before ischaemia and at 20 minutes of reperfusion. FMD (percentage change from baseline diameter) was compared statistically by ANOVA. IR alone caused a significant reduction in FMD (5.9±0.7% pre- versus 2.2±0.4% post-IR, n=9, P<0.001). This reduction was prevented by RPostC (5.8±0.4% pre- versus 5.4±0.3% post-IR, n=8, P>0.05). Systemic phentolamine blocked the protective effects of RPostC (FMD 6.1±0.5% pre- versus 2.0±0.3% post-IR, n=7, P<0.001). These data indicate, for the first time in humans, that protection from RPostC depends on preservation of adrenergic signalling. Alpha blockade neutralises one of the endogenous mechanisms of ischemic protection in humans; the clinical consequences of this remain to be determined.
Impact of blood pressure cuff inflation rates on flow-mediated dilatation and contralateral arm response
