Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning

Author:

Hauerslev Marie1,Mørk Sivagowry Rasalingam12,Pryds Kasper12,Contractor Hussain2,Hansen Jan1,Jespersen Nichlas Riise1,Johnsen Jacob1,Heusch Gerd3,Kleinbongard Petra3,Kharbanda Rajesh2,Bøtker Hans Erik1,Schmidt Michael Rahbek1

Affiliation:

1. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

2. Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

3. Institute for Pathophysiology, West German Heart and Vascular Center, University School of Medicine Essen, Essen, Germany

Abstract

Remote ischemic conditioning (RIC) protects against sustained myocardial ischemia. Because of overlapping mechanisms, this protection may be altered by glyceryl trinitrate (GTN), which is commonly used in the treatment of patients with chronic ischemic heart disease. We investigated whether long-term GTN treatment modifies the protection by RIC in the rat myocardium and human endothelium. We studied infarct size (IS) in rat hearts subjected to global ischemia-reperfusion (I/R) in vitro and endothelial function in healthy volunteers subjected to I/R of the upper arm. In addition to allocated treatment, rats were coadministered with reactive oxygen species (ROS) or nitric oxide (NO) scavengers. Rats and humans were randomized to 1) control, 2) RIC, 3) GTN, and 4) GTN + RIC. In protocols 3 and 4, rats and humans underwent long-term GTN treatment for 7 consecutive days, applied subcutaneously or 2 h daily transdermally. In rats, RIC and long-term GTN treatment reduced mean IS (18 ± 12%, P = 0.007 and 15 ± 5%, P = 0.002) compared with control (35 ± 13%). RIC and long-term GTN treatment in combination did not reduce IS (29 ± 12%, P = 0.55 vs. control). ROS and NO scavengers both attenuated IS reduction by RIC and long-term GTN treatment. In humans, I/R reduced endothelial function ( P = 0.01 vs. baseline). Separately, RIC and long-term GTN prevented the reduction in endothelial function caused by I/R; given in combination, prevention was lost. RIC and long-term GTN treatment both protect against rat myocardial and human endothelial I/R injury through ROS and NO-dependent mechanisms. However, when given in combination, RIC and long-term GTN treatment fail to confer protection. NEW & NOTEWORTHY Remote ischemic conditioning (RIC) and long-term glyceryl trinitrate (GTN) treatment protect against ischemia-reperfusion injury in both human endothelium and rat myocardium. However, combined application of RIC and long-term GTN treatment abolishes the individual protective effects of RIC and GTN treatment on ischemia-reperfusion injury, suggesting an interaction of clinical importance.

Funder

Foundation Leducp

Aarhus University

Novo Nordisk Foundation

Grosserer A.V. Lykfeldt og Hustrus Legat

Familien Hede Nielsen Fonden

Eva og Henry Frænkels Mindefond

Oticon Fonden

Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Fond

Fonden af 1870

Department of Clinical Medicine, University of Aarhus

The Danish Council for Independent Research

Else og Mogens Wedell-Wedellsborgs Fond

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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