Abstract 41: Vagal Nerve Stimulation Attenuates Myocardial Ischemia - Reperfusion Injury by Inhibiting the Mitochondrial Permeability Transition Pore
Background: Reperfusion is considered to be the treatment of choice in patients admitted with acute myocardial infarction. However, reperfusion itself activates a variety of pathological factors leading to various consequences which are collectively termed as reperfusion injury, especially after interventional procedures such as PTCA or coronary artery bypass graft surgery. Hence any drug or intervention preventing reperfusion injury would be considered to be a clinically useful tool. Vagal nerve stimulation (VS) has been demonstrated to exert protective effects against both acute and chronic myocardial ischemia. Here we demonstrate a novel function for VS in protecting the reperfusion heart injury through inhibition of the mitochondrial permeability transition pore (PTP).
Methods: Under anesthesia, rats were either preconditioned with VS (0.1 ms at 10 Hz) (pVS-MI group) or with sham stimulation (SS-MI) for 10 min followed by 30 min of left coronary artery occlusion and 120 min of reperfusion. To study the changes in hemodynamic functions with VS, hearts from different group of rats were perfused in isolated perfusion mode under isovolumetric condition after stimulating the vagal nerve for 10 min in-vivo.
Results: VS treatment induced a significant reduction in the myocardial infarct size compared to SS-MI group (30.3 ± 4.1% vs 64.6 ± 5.2%, p < 0.001). VS activated cell survival cascade such as Akt and Bad phosphorylation and prevented Bcl-2 downregulation, thereby inhibiting the opening of PTP. This was further confirmed by inhibition of cytochrome C release and activation of proapoptotic caspase-3. Moreover isolated heart perfusion studies demonstrated a significant improvement in the recovery of LVDP (75 ± 5%, pVS-MI vs 40 ± 7%, SS-MI, p < 0.001) and less increase in EDP (120 ± 10%, pVS-MI vs 350 ± 14%, SS-MI, p < 0.001) with VS treatment. In contrast, all these effects were abolished by pretreatment with a PTP opener, atractyloside. Studies with rat primary-cultured cardiomyocytes using acetylcholine confirmed that VS inhibited the reperfusion-induced PTP opening.
Conclusion: VS prevents the reperfusion heart injury through inhibition of pathological PTP opening, thus suggesting a role for VS treatment in clinical practice.