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Treatment with new organic nitrites in pulmonary hypertension of acute experimental pulmonary embolism
Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.ORCID iD: 0000-0002-8461-5074
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
2019 (English)In: Pharmacology research & perspectives, E-ISSN 2052-1707, Vol. 7, no 1, article id e00462Article in journal (Refereed) Published
Abstract [en]

Acute pulmonary embolism may cause right heart failure due to increased pulmonary vascular resistance and arterial hypoxemia. Effective vasodilator therapy of the pulmonary hypertension is highly needed. Therefore, we investigated the effects of a newly developed effective pulmonary vasodilator, the organic mononitrites of 1,2-propanediol (PDNO), in a rabbit model of acute pulmonary embolism. In anesthetized and ventilated rabbits, systemic and pulmonary hemodynamics, exhaled nitric oxide (NO), plasma nitrite concentration, and blood gases were monitored. First, dose response experiments with intravenous and left heart ventricle infusions of PDNO and inorganic nitrite were done in naive animals and in pulmonary hypertension induced by a thromboxane A(2) analogue. Second, acute pulmonary embolism was induced and either PDNO or placebo were administered intravenously within 20 minutes and evaluated within 1 hour after pulmonary embolization. PDNO intravenously, in contrast to inorganic nitrite intravenously, increased exhaled NO and counteracted pulmonary hypertension and vasodilated the systemic circulation, dose-dependently, thereby showing efficient NO donation. Pulmonary embolization induced pulmonary hypertension and gas exchange disturbances. PDNO significantly decreased and normalized pulmonary vascular resistance and the right ventricle rate-pressure product, without causing tolerance, with no significant side effects on the systemic circulation, nor on blood-gas values or on methemoglobin formation. In conclusion, PDNO is a NO donor and an efficient vasodilator in the pulmonary circulation. Treatment with this or similar organic nitrites intravenously may be a future option to avoid right heart failure in life-threatening acute pulmonary embolism.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019. Vol. 7, no 1, article id e00462
Keywords [en]
U46619, alkyl nitrites, chromatography, high pressure liquid, hypertension, inorganic nitrite, lung, nitric oxide, nitric oxide donors, nitrites, organic nitrites, pulmonary, pulmonary circulation, pulmonary embolism
National Category
Anesthesiology and Intensive Care Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:oru:diva-72042DOI: 10.1002/prp2.462ISI: 000459169800014PubMedID: 30693089Scopus ID: 2-s2.0-85060576741OAI: oai:DiVA.org:oru-72042DiVA, id: diva2:1288008
Funder
Swedish Heart Lung FoundationSwedish Society for Medical Research (SSMF), P14-0170Swedish Research Council, 07919Lars Hierta Memorial FoundationSwedish National Space Board
Note

Funding Agencies:

Fraenckel's foundation for Medical Research  

European Space Agency 

Region Örebro län ALF grants

Available from: 2019-02-12 Created: 2019-02-12 Last updated: 2019-06-19Bibliographically approved

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Nilsson, Kristofer F.

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