4.6 Article

Co-dependence of the neural and humoral pathways in the mechanism of remote ischemic conditioning


Volume 111, Issue 4, Pages -


DOI: 10.1007/s00395-016-0568-z


Myocardial infarction; Remote ischemic conditioning; Autonomic nervous system; Vagus nerve; Intrinsic cardiac ganglia


  1. British Heart Foundation [FS12/70/30009]
  2. British Heart Foundation [CS/14/3/31002] Funding Source: researchfish
  3. Medical Research Council [MR/J00457X/1, MC_G1002673] Funding Source: researchfish
  4. National Institute for Health Research [NF-SI-0510-10164] Funding Source: researchfish
  5. MRC [MC_G1002673, MR/J00457X/1] Funding Source: UKRI

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The cardioprotection afforded by remote ischaemic conditioning (RIC) is mediated via a complex mechanism involving sensory afferent nerves, the vagus nerve, and release of a humoral blood-borne factor. However, it is unknown whether release of the protective factor depends on vagal activation or occurs independently. This study aimed to evaluate the co-dependence of the neural and humoral pathways of RIC, focussing on the vagus nerve and intrinsic cardiac ganglia. In the first study, anesthetised rats received bilateral cervical vagotomy or sham-surgery immediately prior to RIC (4 9 5 min limb ischemia-reperfusion) or sham-RIC. Venous blood plasma was dialysed across a 12-14 kDa membrane and dialysate perfused through a naive-isolated rat heart prior to 35-min left anterior descending ischemia and 60-min reperfusion. In the second study, anesthetised rats received RIC (4 9 5-min limb ischemia-reperfusion) or control (sham-RIC). Dialysate was prepared and perfused through a naive-isolated rat heart in the presence of the ganglionic blocker hexamethonium or muscarinic antagonist atropine, prior to ischemia-reperfusion as above. Dialysate collected from RIC-treated rats reduced infarct size in naive rat hearts from 40.7 +/- 6.3 to 23.7 +/- 3.1 %, p < 0.05. Following bilateral cervical vagotomy, the protection of RIC dialysate was abrogated (42.2 +/- 3.2 %, p < 0.05 vs RIC dialysate). In the second study, the administration of 50-mu M hexamethonium (45.8 +/- 2.5 %) or 100-nM atropine (36.5 +/- 3.4 %) abrogated the dialysate-mediated protection. Release of a protective factor following RIC is dependent on prior activation of the vagus nerve. In addition, this factor appears to induce cardioprotection via recruitment of intrinsic cardiac ganglia.


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