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Organic mononitrites of 1,2-propanediol act as an effective NO-releasing vasodilator in pulmonary hypertension and exhibit no cross-tolerance with nitroglycerin in anesthetized pigs
Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Physiology and Pharmacology, Karolinska Institutet, 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 Anaesthesiology and Intensive Therapy, Wroclaw Medical University, Wroclaw, Poland.
Department of Anesthesia and Intensive Care, Danderyd Hospital, Stockholm, Sweden.
Department of Anaesthesiology and Intensive Therapy, Wroclaw Medical University, Wroclaw, Poland.
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2018 (English)In: Drug Design, Development and Therapy, ISSN 1177-8881, E-ISSN 1177-8881, Vol. 12, p. 685-694Article in journal (Refereed) Published
Abstract [en]

Purpose: Clinically available intravenous (IV) nitric oxide (NO) donor drugs such as nitroglycerin (GTN) cause systemic hypotension and/or tolerance development. In a porcine model, novel NO donor compounds - the organic mononitrites of 1,2-propanediol (PDNO) were compared to GTN with regard to pulmonary selectivity and tolerance development. The vasodilatory effects of inorganic nitrite were investigated.

Materials and methods: In anesthetized piglets, central hemodynamics were monitored. At normal pulmonary vascular resistance (PVR), IV infusions of PDNO (15-60 nmol kg(-1) min(-1)), GTN (13-132 nmol kg(-1) min(-1)), and inorganic nitrite (dosed as PDNO) were administered. At increased PVR (by U46619 IV), IV infusions of PDNO (60-240 nmol kg(-1) min(-1)) and GTN (75-300 nmol kg(-1) min(-1)) before and after a 5 h infusion of GTN (45 nmol kg-1 min-1) were given.

Results: At normal PVR, PDNO (n=12) and GTN (n=7) caused significant dose-dependent decreases in mean systemic and pulmonary arterial pressures, whereas inorganic nitrite (n=13) had no significant effect. At increased PVR, PDNO (n=6) and GTN (n=6) significantly decreased mean systemic and pulmonary pressures and resistances, but only PDNO reduced the ratio between pulmonary and systemic vascular resistances significantly. After the 5 h GTN infusion, the hemodynamic response to GTN infusions (n=6) was significantly suppressed, whereas PDNO (n=6) produced similar hemodynamic effects to those observed before the GTN infusion.

Conclusion: PDNO is a vasodilator with selectivity for pulmonary circulation exhibiting no cross-tolerance to GTN, but GTN causes non selective vasodilatation with substantial tolerance development in the pulmonary and systemic circulations. Inorganic nitrite has no vasodilatory properties at relevant doses.

Place, publisher, year, edition, pages
DOVE Medical Press Ltd. , 2018. Vol. 12, p. 685-694
Keywords [en]
nitrites, nitrates, nitric oxide donors, tachyphylaxis, PDNO
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:oru:diva-66657DOI: 10.2147/DDDT.S149727ISI: 000428802300004PubMedID: 29636602Scopus ID: 2-s2.0-85044831003OAI: oai:DiVA.org:oru-66657DiVA, id: diva2:1198900
Funder
Swedish Heart Lung FoundationSwedish Society for Medical Research (SSMF)
Note

Funding Agencies:

European Space Agency  

Fraenckel Foundation  

Lars Hierta Foundation  

Karolinska Institutet  

Region Örebro County  

CF Research and Consulting AB, Stockholm, Sweden  

Available from: 2018-04-19 Created: 2018-04-19 Last updated: 2018-04-19Bibliographically approved

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Nilsson, Kristofer F.

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