Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect

Background: In spite of recent advances in coronary interventional therapy, reperfusion injury is still considered to be a major problem in patients undergoing surgical procedures, such as bypass grafting. Here we demonstrate a novel therapeutic strategy against ischemia-reperfusion injury: vagally mediated prevention of reperfusion-induced opening of mitochondrial permeability transition pore. Methods: We investigated the effects of efferent vagal stimulation on myocardial reperfusion injury with ex vivo and in vitro rat models. In the ex vivo model the hearts were perfused with intact vagal innervation, which allowed us to study the effects of the vagal nerve on the heart without other systemic effects. Results: Compared with sham stimulation, vagal stimulation exerted a marked anti-infarct effect irrespective of the heart rate (34% ± 6% vs 85% ± 9% at a heart rate of 300 beats/min, 37% ± 4% vs 43% ± 5% at a heart rate of 250 beats/min, and 39% ± 4% vs 88% ± 7% at a heart rate of 350 beats/min) after a 30-minute period of global ischemia, activated cell-survival Akt cascade, prevented downregulation of the antiapoptotic protein Bcl-2, and suppressed cytochrome-c release and caspase-3 activation. Furthermore, vagal stimulation-treated hearts exhibited a significant improvement in left ventricular developed pressure (78 ± 5 vs 45 ± 8 mm Hg) and a significant attenuation in an incremental change in left ventricular end-diastolic pressure during reperfusion. These beneficial effects of vagal stimulation were abolished by a permeability transition pore opener, atractyloside. In the in vitro study with primary-cultured cardiomyocytes, acetylcholine prevented a reoxygenation-induced collapse in mitochondrial transmembrane potential through inhibition of permeability transition pore opening. Conclusion: Vagal stimulation would be a potential adjuvant therapy for the rescue of ischemic myocardium from reperfusion injury, and the protective effects are independent of its bradycardiac effects.