Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning.

This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia-reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 µM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia-reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPCeff = 0.36 ± 0.03 µM vs C eff = 0.04 ± 0.04 µM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia-reperfusion injury (cell death = 45 ± 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors.

Remote ischaemic conditioning: cardiac protection from afar.

For patients with ischaemic heart disease, remote ischaemic conditioning may offer an innovative, non-invasive and virtually cost-free therapy for protecting the myocardium against the detrimental effects of acute ischaemia-reperfusion injury, preserving cardiac function and improving clinical outcomes. The intriguing phenomenon of remote ischaemic conditioning was first discovered over 20 years ago, when it was shown that the heart could be rendered resistant to acute ischaemia-reperfusion injury by applying one or more cycles of brief ischaemia and reperfusion to an organ or tissue away from the heart - initially termed 'cardioprotection at a distance'. Subsequent pre-clinical and then clinical studies made the important discovery that remote ischaemic conditioning could be elicited non-invasively, by inducing brief ischaemia and reperfusion to the upper or lower limb using a cuff. The actual mechanism underlying remote ischaemic conditioning cardioprotection remains unclear, although a neuro-hormonal pathway has been implicated. Since its initial discovery in 1993, the first proof-of-concept clinical studies of remote ischaemic conditioning followed in 2006, and now multicentre clinical outcome studies are underway. In this review article, we explore the potential mechanisms underlying this academic curiosity, and assess the success of its application in the clinical setting.