15 February 2020 by Claes Frostell

NO-releasing organic nitrites in acute pulmonary hypertension: investigation of tolerance development in an experimental porcine model

Background: Organic nitrates, e.g. nitroglycerin, exhibit extensive tolerance development to itself and other organic nitrates (i.e. cross-tolerance) in long-term applications. The recently developed nitric oxide donor for intravenous administration, the organic mononitrites of 1,2-propanediol (PDNO), has been shown to have some selectivity for vasodilation in the pulmonary circulation in several relevant models of acute pulmonary hypertension. Interestingly, cross-tolerance in pulmonary and systemic vasodilation between nitroglycerin and PDNO did not develop in experimental acute pulmonary hypertension in pigs (Nilsson et al, 2018, Drug Des Devel Ther). The aim of the present study was to investigate if PDNO developed tolerance to itself in acute pulmonary hypertension induced by multiorgan failure.

Methods: In anesthetized, mechanically ventilated and instrumented pigs (n=6), the effects of PDNO (15-60 nmol kg-1 min-1) on pulmonary and systemic arterial pressures and the concentration of nitric oxide in exhaled gas (chemiluminescence) were compared at baseline and after a combination of aortic cross-clamping (90 min) followed by reperfusion and a 10 hours intravenous infusion of PDNO (45 nmol kg-1 min-1).

Results: Intravenous PDNO caused a similar increase of the concentration of nitric oxide in exhaled gas and decrease in systemic arterial pressure before and after the 10 hours infusion of PDNO. At baseline, PDNO in increasing dose only had a slight lowering effect on the normal pulmonary arterial pressure, whereas it completely decreased the increased pulmonary arterial pressure after aortic cross clamping and reperfusion.

Conclusion: Intravenous PDNO was free of tolerance development to itself in a clinically relevant model of acute pulmonary hypertension. This is an advantageous characteristic of the substance compared to organic nitrates in clinical use.

Conflict-of-interest: Authors CF and KFN report financial interest in the subject matter (PDNO).

About the author


profile picture of Claes Frostell

Claes Frostell

Professor, Consultant

Karolinska Institute at Danderyd Hospital

Sweden

Key Contributors

Frostell C, Gozdzik W, Zielinski S; Skrzypczak P, Ratajczak K, Albert J, Nilsson KF; Dept of Anesthesia and Intensive Care, Karolinska Institutet at Danderyd Hospital (Stockholm, Sweden), Wroclaw Medical University, Dept and Clinic of Surgery Wroclaw Univ of Environmental and Life Sciences (Wroclaw, Poland), Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University (Örebro, Sweden).


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