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Modulation of nitric oxide expression with methylene blue does not improve outcome after hypovolemic cardiac arrest
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, 02114 Boston, Massachusetts, USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
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2011 (English)In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 82, no 10, 1344-1349 p.Article in journal (Refereed) Published
Abstract [en]

Aim of the study: We recently reported that female sex protects against cerebral and cardiac injury after hypovolemiccardiac arrest (CA), independent of sex hormone effects. As female sex was also associated with a smaller increase in inducible and neuronal nitric oxide synthase (NOS), we hypothesised that nitric oxide inhibition with methylene blue (MB) improves the outcome, primarily in male animals. Methods: Twenty sexually immature piglets (10 males and 10 females) were bled to mean arterial blood pressure of 35 mmHg, and were subjected to 2 min of untreated CA followed by 8 min of open chest cardiopulmonary resuscitation (CPR). Volume resuscitation was started during CPR with intravenous administration of 3 ml kg(-1) hypertonic saline-dextran. Methyleneblue was then administered as bolus of 2.5 mg kg(-1) over 20 min, followed by 1.5 mg kg(-1) infusion over 40 min. Historical data from 21 animals were used as control (no MB). Hemodynamic parameters, myocardial injury (troponin I), and short-term survival (3-h) were evaluated. Histopathological evaluation of heart specimens was performed. Results: There were no differences between male and female animals in survival or resuscitation rate. After CA female pigletshad significantly greater systolic and mean arterial pressures, and had lower troponin I plasma concentrations compared to malepiglets, with or without MB. No difference was observed in histopathological analysis of heart specimens between sexes. Conclusions: After resuscitation from hypovolemic CA, female sex protects against cardiac injury, independent of sex hormones. Modulation of NO expression with MB does not improve survival or myocardial histological injury in either sex. 

Place, publisher, year, edition, pages
2011. Vol. 82, no 10, 1344-1349 p.
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-146313DOI: 10.1016/j.resuscitation.2011.04.027ISI: 000296168700020PubMedID: 21636201OAI: oai:DiVA.org:uu-146313DiVA: diva2:397993
Available from: 2011-02-16 Created: 2011-02-16 Last updated: 2014-08-15Bibliographically approved
In thesis
1. Sex Differences in Cardiac and Cerebral Damage after Hypovolemic Cardiac Arrest
Open this publication in new window or tab >>Sex Differences in Cardiac and Cerebral Damage after Hypovolemic Cardiac Arrest
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Resuscitation from haemorrhagic shock and the subsequent circulatory arrest remains a major clinical challenge in the care of trauma patients. Numerous experimental studies in sexually mature animals have shown a gender dimorphism in response to trauma and haemorrhagic shock. The first study was designed to evaluate sex differences in outcome after resuscitation from hypovolemic circulatory arrest. We intended to examine innate sex differences, and chose to study sexually immature animals. The study showed that cerebral cortical blood flow was greater, blood-brain-barrier was better preserved and neuronal injury was smaller in female as compared to male piglets. The second study demonstrated that female sex was associated with enhanced haemodynamic response, cardioprotection, and better survival. This cardioprotective effect was observed despite comparable estradiol and testosterone levels in male and female animals, indicating an innate gender-related cardioprotection. In both studies (I and II) female sex was associated with a smaller increase in the cerebral expression of inducible and neuronal nitric oxide synthase (iNOS and nNOS). Thus in the study III we tested the hypothesis that exogenously administered 17β-estradiol (E2) could improve neurological outcome by NOS modulation. The results showed that compared with the control group, animals in the E2 group exhibited a significantly smaller increase in nNOS and iNOS expression, a smaller blood-brain-barrier disruption and a mitigated neuronal injury. There was also a significant correlation between nNOS and iNOS levels and neuronal injury. A hypothesis if female-specific cardioprotection may be attributed to a smaller NOS activity was tested in study IV. The animals received methylene blue (MB) during CPR, but were otherwise treated according to the same protocol as studies I-II. The female-specific cardioprotection could be attributed to a smaller NOS activity, but NOS inhibition with MB did not improve survival or myocardial injury, although it abated the difference between the sexes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 654
Keyword
Cardiopulmonary resuscitation, sex, haemorrhage, neuronal damage, estradiol, hypertonic saline, nitric oxide, methylene blue
National Category
Medical and Health Sciences
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-146314 (URN)978-91-554-8028-8 (ISBN)
Public defence
2011-04-28, Hedstrandsalen, Akademiska sjukhuset, entrance no. 70, Uppsala, 09:15 (Swedish)
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Available from: 2011-04-08 Created: 2011-02-16 Last updated: 2011-05-05Bibliographically approved

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Semenas, EgidijusThiblin, IngemarRubertsson, StenWiklund, Lars

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