Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury

Pedersen, C. M. et al. (2016) Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury. British Journal of Clinical Pharmacology, 81(6), pp. 1037-1045. (doi: 10.1111/bcp.12882) (PMID:26750458)

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.

• Item Type: Articles
• Additional Information: We are grateful to the staff of the Welcome Trust Clinical Research Facility at the Royal Infirmary of Edinburgh and to the Institute of Clinical Medicine, Aarhus University Hospital Skejby. DEN is supported by the British Heart Foundation (CH/09/002) and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). CMP received funding from the Danish Agency for Science, Technology and Innovation, Region Midtjyllands Sundhedsvidenskabelige Forskningsfond, Det Classenske Fideicomis Jubilæumsfond, Snedkermester Sophus Jacobsen og hustru Astrid Jacobsen's Fond, Civilingeniør Stenild Hjorth's enke Else Hjorth's Fond, The A.P. Møller Foundation for the Advancement of Medical Science, Kirsten Antonius' Mindelegat and Institute of Clinical Medicine, University of Aarhus. RKK is funded by the NIHR Oxford Comprehensive Biomedical Research Centre.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lang, Professor Ninian and Newby, Professor David
• Authors: Pedersen, C. M., Venkatasubramanian, S., Vase, H., Hyldebrandt, J. A., Contractor, H., Schmidt, M. R., Bøtker, H. E., Cruden, N. L., Newby, D. E., Kharbanda, R. K., and Lang, N. N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: British Journal of Clinical Pharmacology
• Publisher: Wiley
• ISSN: 0306-5251
• ISSN (Online): 1365-2125
• Published Online: 11 January 2016
• Copyright Holders: Copyright © 2016 The British Pharmacological Society
• First Published: First published in British Journal of Clinical Pharmacology 81(6):1037-1045
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher