Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury

AIM Ischaemia-reperfusion injury (IRI) causes impaired endothelial function and is a major component of the adverse effects of reperfusion following myocardial infarction. Rotigaptide increases gap junction conductance via connexin-43. We tested the hypothesis that rotigaptide reduces experimental myocardial infarction size and ameliorates endothelial IRI in humans. METHODS Myocardial infarction study: porcine myocardial infarction was achieved by catheter-induced occlusion of the left anterior descending artery. In a randomized double-blind study, rotigaptide (n = 9) or placebo (n = 10) was administered intravenously as a 10 min bolus prior to reperfusion and continuously during 2 h of reperfusion. Myocardial infarction size (IS) was assessed as proportion of the area at risk (AAR). Human translational study: forearm IRI was induced in the presence or absence of intra-arterial rotigaptide. In a randomized double-blind study, forearm arterial blood flow was measured at rest and during intra-arterial infusion of acetylcholine (5-20 mu g min(-1); n = 11) or sodium nitroprusside (2-8 mg min-1; n = 10) before and after intra-arterial infusion of placebo or rotigaptide, and again following IRI. RESULTS Myocardial infarction study: Rotigaptide treatment was associated with a reduction of infarct size (IS/ AAR[%]: 18.7 +/- 4.1 [rotigaptide] vs. 43.6 +/- 4.2 [placebo], P = 0.006). Human translational study: Endothelium-dependent vasodilatation to acetylcholine was attenuated after ischaemia-reperfusion in the presence of placebo (P = 0.007), but not in the presence of rotigaptide (P = NS). Endothelium-independent vasodilatation evoked by sodium nitroprusside was unaffected by IRI or rotigaptide (P = NS). CONCLUSIONS Rotigaptide reduces myocardial infarction size in a porcine model and protects from IRI-related endothelial dysfunction in man. Rotigaptide may have therapeutic potential in the treatment of myocardial infarction. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Ischaemia-reperfusion injury reflects the paradoxical injury associated with restoration of blood flow to an ischaemic organ. Connexins may play a pivotal role in ischaemia-reperfusion injury. A means to prevent this paradoxical injury should translate into improved clinical outcomes for a wide range of patients including those treated for ischaemic stroke, myocardial infarction or for those undergoing solid organ transplantation. WHAT THIS STUDY ADDS Rotigaptide, a modulator of connexin 43 phosphorylation, is associated with a marked reduction in porcine myocardial infarction size when administered at the time of reperfusion. Ischaemia-reperfusion injury reduces endothelium-dependent vasodilatation in the human forearm arterial circulation, but this effect is not seen in the presence of rotigaptide. These findings provide important direction for the development of connexinmodulators designed for the limitation of clinically important ischaemia-reperfusion injury.