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Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, e64792- p.Article in journal (Refereed) Published
Abstract [en]

Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34°C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

Place, publisher, year, edition, pages
2013. Vol. 8, no 5, e64792- p.
National Category
Anesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-200585DOI: 10.1371/journal.pone.0064792ISI: 000319435600076PubMedID: 23717659OAI: oai:DiVA.org:uu-200585DiVA: diva2:624334
Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Novel Interventions in Cardiac Arrest: Targeted Temperature Management, Methylene Blue, S-PBN, Amiodarone, Milrinone and Esmolol,  Endothelin and Nitric Oxide In Porcine Resuscitation Models
Open this publication in new window or tab >>Novel Interventions in Cardiac Arrest: Targeted Temperature Management, Methylene Blue, S-PBN, Amiodarone, Milrinone and Esmolol,  Endothelin and Nitric Oxide In Porcine Resuscitation Models
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It is a major clinical problem that survival rates after out-of-hospital cardiac arrest have not markedly improved during the last decades, despite extensive research and the introduction of new interventions. However, recent studies have demonstrated promising treatments such as targeted temperature management (TTM) and methylene blue (MB).

In our first study, we investigated the effect of MB administered during experi-mental cardiopulmonary resuscitation (CPR) in the setting of postponed hypother-mia in piglets. We set out to study if MB could compensate for a delay to establish targeted TTM. The study demonstrated that MB more than compensated for 30 min delay in induction of TTM. The effect of MB added to that of TTM.

The second study examined the effects of TTM and S-PBN on the endothelin system and nitric oxide synthases (NOS) after prolonged CA in a porcine CPR mod-el. The study was designed to understand the cardioprotective mechanism of S-PBN and TTM by their influence on the endothelin system and NOS regulation. We veri-fied for the first time, that these two cardioprotective postresuscitative interventions activate endothelin-1 and its receptors concomitantly with eNOS and nNOS in the myocardium. We concluded that nitric oxide and endothelin pathways are implicated in the postresuscitative cardioprotective effects of TTM.

The third study compared survival and hemodynamic effects of low-dose amio-darone and vasopressin to vasopressin in a porcine hypovolemic CA model. The study was designed to evaluate whether resuscitation with amiodarone and vasopressin compared to vasopressin alone would have an impact on resuscitation success, survival, and hemodynamic parameters after hemorrhagic CA. We found that combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters and smaller myocardial injury compared to resuscitation with vasopressin only.

In our fourth study we planned to compare hemodynamic parameters between the treatment group (milrinone, esmolol and vasopressin; MEV) and control group (vasopressin only) during resuscitation from prolonged cardiac arrest in piglets. The study was designed to demonstrate if MEV treatment improved hemodynamics or cardiac damage compared to controls. We demonstrated that MEV treatment reduced cardiac injury compared with vasopressin alone.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2015. 102 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1056
Keyword
restoration of spontaneous circulation, ROSC, cardiopulmonary resuscitation, CPR, cardiac arrest, methylene blue, MB, S-PBN, mild therapeutic hypothermia, MTH, targeted temperature management, TTM, endothelin, ET-1, ECE-1, ETAR, ETBR, nitric oxide, NO, nitric oxide synthase, NOS, eNOS, iNOS, nNOS, porcine, amiodarone, hypovolemia, milrinone, vasopressin, esmolol, epinephrine
National Category
Anesthesiology and Intensive Care Cell and Molecular Biology Physiology Cardiac and Cardiovascular Systems
Research subject
Anaesthesiology and Intensive Care; Medical Cell Biology; Cardiology
Identifiers
urn:nbn:se:uu:diva-236312 (URN)978-91-554-9116-1 (ISBN)
Public defence
2015-01-30, Hedstrandssalen, Akademiska sjukhuset, Ing. 70, Uppsala, 13:15 (Swedish)
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Supervisors
Available from: 2015-01-08 Created: 2014-11-17 Last updated: 2015-02-03

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Zoerner, FrankWiklund, LarsMiclescu, AdrianaMartijn, Cecile

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