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

Marie Hauerslev; Sivagowry Rasalingam Mørk; Kasper Pryds; Hussain Contractor; Jan Hansen; Nichlas Riise Jespersen; Jacob Johnsen; Gerd Heusch; Petra Kleinbongard; Rajesh Kharbanda; Hans Erik Bøtker; Michael Rahbek Schmidt

doi:10.1152/ajpheart.00114.2018

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

Marie Hauerslev, Sivagowry Rasalingam Mørk, Kasper Pryds, Hussain Contractor, Jan Hansen, Nichlas Riise Jespersen, Jacob Johnsen, Gerd Heusch, Petra Kleinbongard, Rajesh Kharbanda, Hans Erik Bøtker, Michael Rahbek Schmidt

Department of Clinical Medicine - The Department of Cardiological Medicine B

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	American Journal of Physiology - Heart and Circulatory Physiology
Volume	315
Issue	1
Pages (from-to)	H150-H158
ISSN	1522-1539
DOIs	https://doi.org/10.1152/ajpheart.00114.2018
Publication status	Published - 1 Jul 2018

Keywords

Cardioprotection
Endothelial function
Glyceryl trinitrate
Ischemic preconditioning
Myocardial infarction
Remote ischemic conditioning

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10.1152/ajpheart.00114.2018

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Hauerslev, M., Mørk, S. R., Pryds, K., Contractor, H., Hansen, J., Jespersen, N. R., Johnsen, J., Heusch, G., Kleinbongard, P., Kharbanda, R., Bøtker, H. E., & Schmidt, M. R. (2018). Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning. American Journal of Physiology - Heart and Circulatory Physiology, 315(1), H150-H158. https://doi.org/10.1152/ajpheart.00114.2018

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title = "Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning",

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.",

keywords = "Cardioprotection, Endothelial function, Glyceryl trinitrate, Ischemic preconditioning, Myocardial infarction, Remote ischemic conditioning",

author = "Marie Hauerslev and M{\o}rk, {Sivagowry Rasalingam} and Kasper Pryds and Hussain Contractor and Jan Hansen and Jespersen, {Nichlas Riise} and Jacob Johnsen and Gerd Heusch and Petra Kleinbongard and Rajesh Kharbanda and B{\o}tker, {Hans Erik} and Schmidt, {Michael Rahbek}",

year = "2018",

month = jul,

day = "1",

doi = "10.1152/ajpheart.00114.2018",

language = "English",

volume = "315",

pages = "H150--H158",

journal = "American Journal of Physiology - Heart and Circulatory Physiology",

issn = "1522-1539",

publisher = "American Physiological Society",

number = "1",

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Hauerslev, M, Mørk, SR , Pryds, K, Contractor, H, Hansen, J , Jespersen, NR , Johnsen, J, Heusch, G, Kleinbongard, P, Kharbanda, R, Bøtker, HE & Schmidt, MR 2018, 'Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning', American Journal of Physiology - Heart and Circulatory Physiology, vol. 315, no. 1, pp. H150-H158. https://doi.org/10.1152/ajpheart.00114.2018

Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning. / Hauerslev, Marie; Mørk, Sivagowry Rasalingam ; Pryds, Kasper et al.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 315, No. 1, 01.07.2018, p. H150-H158.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning

AU - Hauerslev, Marie

AU - Mørk, Sivagowry Rasalingam

AU - Pryds, Kasper

AU - Contractor, Hussain

AU - Hansen, Jan

AU - Jespersen, Nichlas Riise

AU - Johnsen, Jacob

AU - Heusch, Gerd

AU - Kleinbongard, Petra

AU - Kharbanda, Rajesh

AU - Bøtker, Hans Erik

AU - Schmidt, Michael Rahbek

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

KW - Cardioprotection

KW - Endothelial function

KW - Glyceryl trinitrate

KW - Ischemic preconditioning

KW - Myocardial infarction

KW - Remote ischemic conditioning

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U2 - 10.1152/ajpheart.00114.2018

DO - 10.1152/ajpheart.00114.2018

M3 - Journal article

C2 - 29569958

SN - 1522-1539

VL - 315

SP - H150-H158

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

IS - 1

ER -

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

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Keywords

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