Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury

Abstract

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 μg 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.

Keywords: blood flow; endothelium; myocardial infarction; pharmacology; reperfusion.

© 2016 The British Pharmacological Society.

Figures

Figure 1

Left ventricular myocardial slices stained with Evans blue (area NOT at risk) and triphenyl tetrazolium chloride (TCC). Evans blue dye statining (dark red) delineates area not at risk from infarction (upper regions in these representative slices; left panel = rotigaptide treated animal, right panel = placebo). TTC staining bright red = viable tissue; white colour = infarcted tissue

Figure 2

Human translational study schedule of drug administration and ischaemia/reperfusion timings. ACh: acetylcholine (protocol A); SNP: sodium nitroprusside (protocol B)

Figure 3

Final myocardial infarction size (IS) expressed as a proportion of the area at risk (AAR); P = 0.006, placebo vs. rotigaptide (anova)

Figure 4

Forearm arterial vasomotor responses to intra‐arterial acetylcholine, in the presence and absence of rotigaptide, before and after ischaemia‐reperfusion injury. Two‐way anova baseline blood flow responses at baseline vs. 15 min (left panels) or 45 min (right panels) following reperfusion. baseline, 15 min and 45 min

Figure 5

Forearm arterial vasomotor responses to intra‐arterial sodium nitroprusside, in the presence and absence of rotigaptide, before and after ischaemia‐reperfusion injury. Two‐way anova baseline blood flow responses at baseline vs. 15 min (left panels) or 45 min (right panels) following reperfusion. baseline, 15 min and 45 min