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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

Authors Nilsson KF, Goździk W, Frostell C, Zieliński S, Zielińska M, Ratajczak K, Skrzypczak P, Rodziewicz S, Albert J, Gustafsson LE

Received 22 August 2017

Accepted for publication 17 January 2018

Published 29 March 2018 Volume 2018:12 Pages 685—694

DOI https://doi.org/10.2147/DDDT.S149727

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Georgios D. Panos


Kristofer F Nilsson,1,2 Waldemar Goździk,3 Claes Frostell,4 Stanisław Zieliński,3 Marzena Zielińska,3 Kornel Ratajczak,5 Piotr Skrzypczak,5 Sylwia Rodziewicz,5 Johanna Albert,6 Lars E Gustafsson1,†

1Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 2Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 3Department of Anaesthesiology and Intensive Therapy, Wroclaw Medical University, Wroclaw, Poland; 4Department of Anesthesia and Intensive Care, Danderyd Hospital, Stockholm, Sweden; 5Department and Clinic of Surgery, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland; 6Department of Surgery, Danderyd Hospital, Stockholm, Sweden

Lars E Gustafsson passed away on October 04, 2017

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.

Keywords: nitrites, nitrates, nitric oxide donors, tachyphylaxis, PDNO

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