A Comparative Study of Inhaled Nitric Oxide and an Intravenously Administered Nitric Oxide Donor in Acute Pulmonary Hypertension

Abstract

Purpose

Inhaled nitric oxide (iNO) selectively vasodilates the pulmonary circulation but the effects are sometimes insufficient. Available intravenous (iv) substances are non-selective and cause systemic side effects. The pulmonary and systemic effects of iNO and an iv mono-organic nitrite (PDNO) were compared in porcine models of acute pulmonary hypertension.

Methods

In anesthetized piglets, dose–response experiments of iv PDNO at normal pulmonary arterial pressure (n=10) were executed. Dose–response experiments of iv PDNO (n=6) and iNO (n=7) were performed during pharmacologically induced pulmonary hypertension (U46619 iv). The effects of iv PDNO and iNO were also explored in 5 mins of hypoxia-induced increase in pulmonary pressure (n=2-4).

Results

PDNO (15, 30, 45 and 60 nmol NO kg⁻¹ min⁻¹ iv) and iNO (5, 10, 20 and 40 ppm which corresponded to 56, 112, 227, 449 nmol NO kg⁻¹ min⁻¹, respectively) significantly decreased the U46619-increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) to a similar degree without significant decreases in mean arterial pressure (MAP) or systemic vascular resistance (SVR). iNO caused increased levels of methemoglobin. At an equivalent delivered NO quantity (iNO 5 ppm and PDNO 45 nmol kg⁻¹ min⁻¹ iv), PDNO decreased PVR and SVR significantly more than iNO. Both drugs counteracted hypoxia-induced pulmonary vasoconstriction and they decreased the ratio of PVR and SVR in both settings.

Conclusion

Intravenous PDNO was a more potent pulmonary vasodilator than iNO in pulmonary hypertension, with no severe side effects. Hence, this study supports the potential of iv PDNO in the treatment of acute pulmonary hypertension.

Keywords:

• PDNO
• inhaled NO
• acute pulmonary hypertension
• hypoxia-induced vasoconstriction
• U46619

Acknowledgments

The authors would like to express gratitude to the late professor Lars E. Gustafsson for excellent guidance during the experiments and special thanks to RN Nina Adolfsson for invaluable help with coordination in the laboratory.

Abbreviations

ARDS, acute respiratory distress syndrome; pCO₂, arterial partial pressure of carbon dioxide; pO₂, arterial partial pressure of oxygen; CVP, central venous pressure; CCO, continuous cardiac output; ETCO₂, end-tidal carbon dioxide concentration; ETO₂, end-tidal oxygen concentration; FIO₂, Fraction of Inspired oxygen; HR, heart rate; iNO, inhaled nitric oxide; IQR, interquartile range; IM, intramuscular; iv, intravenous; MAP, mean arterial pressure; MPAP, mean pulmonary arterial pressure; MetHb, methemoglobin; MV, minute volume; NO, nitric oxide; ppm, parts per million; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; TV, tidal volume; U46619, thromboxane A2-mimetic 9,11-dideoxy-9α, 11α-methanoepoxy PGF_2α; PDNO, 1,2-propanediol mono-organic nitrites.

Disclosure

Anna Stene Hurtsén reports grants from Attgeno AB, during the conduct of the study. Kristofer F Nilsson wishes to declare potential financial competing interests due to his roles as co-applicant in three international patents (US 8,552,068, US 8,030,511 and EP 2004576), and co-ownership, consultancy and former board membership of Attgeno AB, pertaining to the current subject matter; reports grants and personal fees from Attgeno AB, Stockholm, Sweden, during the conduct of the study; and has another patent pending: UK Patent Application No. 1819298.9. The authors report no other conflicts of interest in this work.