BACKGROUND: The heart can be protected against prolonged ischemia by applying brief episodes of intermittent ischaemia to an organ or tissue remote from the heart (termed remote ischaemic conditioning, remote-IPC). This has the advantage of being able to be non-invasively applied using a blood pressure cuff, and proof-of-concept clinical studies have recently provided encouraging results using remote-IPC. The mediators of remote-IPC are uncertain, but both neural and humoral pathways have been implicated in animal studies. The present study examined the molecular mechanisms of myocardial protection afforded by remote-ischaemic preconditioning (RIPC) in the hind-limb of sheep, and whether the combination of a novel cardioprotectant flavonol NP202 with RIPC produced additional cardioprotection above that afforded by individual treatments alone.
METHODS: Anaesthetized sheep were randomly allocated to 4 groups: sham conditioning ± NP202 or RIPC ± NP202 (each n=4). RIPC consisted of 3x5 min occlusions of the iliac artery. Subsequently, animals underwent coronary artery occlusion for 1 h then, 5 min before reperfusion animals, were treated with vehicle or NP202 (6.6 mg/kg, IV). At the end of 3 h reperfusion infarct size was measured, and non-infarcted area-at-risk (AAR) myocardium (the area that can be rescued by treatment) was collected to assess activation of protein kinases.
RESULTS: Separately, RIPC and NP202 significantly reduced infarct size compared to control (by 45±10% and 51±16 %, respectively, P<0.05). No synergistic effect of combined RIPC and NP202 treatment on infarct size reduction was observed (infarct size was reduced by a comparable 42±10%). Myocardial I/R also induced pro-survival (ERK1/2, AKT) and pro-injury (p38, JNK) kinase phosphorylation, however no significant modulatory effect of RIPC and NP202 on kinase phosphorylation could be demonstrated.
CONCLUSIONS: RIPC and NP202 are effective individual treatment strategies to reduce myocardial I/R injury. However, combining both therapies did not offer greater cardioprotection than either treatment alone.
DISCLOSURES: CN May is a shareholder in NeuProtect, a company which holds a patent for use of flavonols as a treatment for myocardial ischaemia-reperfusion injury.