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Inhalation of NO during myocardial ischemia reduces infarct size and improves cardiac function

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Abstract

Purpose

Bioactive NO carriers in circulating blood formed during NO inhalation selectively distribute blood flow to areas in need, and may thus improve collateral perfusion to the area-at-risk in acute myocardial infarction (AMI). Here, we tested the hypothesis that NO inhalation during the ischemic phase of AMI may improve left ventricular function and reduce infarct size in rats.

Methods

Following left anterior descending coronary artery (LAD) occlusion, rats received 50 ppm NO for 2 h of ischemia, during subsequent 3 h of reperfusion, or for 5 h of ischemia and reperfusion. Effects of inhaled NO were compared to those of intravenous nitrite as a putative carrier formed during NO inhalation. Downstream signaling via soluble guanylate cyclase was tested by inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).

Results

NO inhalation during myocardial ischemia increased left ventricular systolic pressure, contractility, relaxation, and cardiac output, and reduced myocardial infarction size and area-at-risk as compared to untreated controls. NO inhalation during the reperfusion phase caused a comparable protective effect. Combined inhalation during ischemia and reperfusion did not further improve left ventricular hemodynamics, but had an additive protective effect on the myocardial area-at-risk. NO inhalation increased circulating nitrite levels, and mimicking of this effect by intravenous nitrite infusion achieved similar protection as NO inhalation during myocardial ischemia, while ODQ blocked the protective NO effect.

Conclusions

Inhalation of NO during myocardial ischemia improves left ventricular function and reduces infarct size by mechanisms that increase levels of circulating nitrite and involve soluble guanylate cyclase. NO inhalation may represent a promising early intervention in AMI.

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Acknowledgments

This study was supported by the Canadian Institutes of Health Research (CIHR MOP #93584), the Heart and Stroke Foundation Ontario (NA #6900), and the McLaughlin Foundation.

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Authors and Affiliations

  1. Institute of Physiology, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Nils Neye, Fabian Enigk, Helmut Habazettl & Wolfgang M. Kuebler

  2. Department of Anesthesiology and Operative Intensive Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Fabian Enigk

  3. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Sruti Shiva

  4. Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Mark T. Gladwin

  5. Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Mark T. Gladwin

  6. German Heart Institute Berlin, Berlin, Germany

    Helmut Habazettl, Hermann Kuppe & Wolfgang M. Kuebler

  7. Institute for Stroke and Dementia Research, Ludwig Maximilians University, Munich, Germany

    Nikolaus Plesnila

  8. The Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 209 Victoria Street, Toronto, ON, M5B 1W8, Canada

    Wolfgang M. Kuebler

  9. Department of Surgery, University of Toronto, Toronto, ON, Canada

    Wolfgang M. Kuebler

  10. Department of Physiology, University of Toronto, Toronto, ON, Canada

    Wolfgang M. Kuebler

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  1. Nils Neye
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Correspondence to Wolfgang M. Kuebler.

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Neye, N., Enigk, F., Shiva, S. et al. Inhalation of NO during myocardial ischemia reduces infarct size and improves cardiac function. Intensive Care Med 38, 1381–1391 (2012). https://doi.org/10.1007/s00134-012-2605-1

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  • DOI: https://doi.org/10.1007/s00134-012-2605-1

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