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Inhaled nitric oxide in adults: Biology and indications for use

Author
James R Klinger, MD
Section Editor
Jess Mandel, MD
Deputy Editor
Geraldine Finlay, MD

INTRODUCTION

Nitric oxide (NO) is a naturally occurring vasodilator produced by vascular endothelial cells. In patients with pulmonary arterial hypertension (PAH), inhaled NO has an established role in vasoreactivity testing. Inhaled NO has also been proposed as a long-term therapy for PAH and possibly other types of pulmonary hypertension (PH) [1], and is occasionally used as a rescue therapy for severely hypoxemic patients both with and without an established diagnosis of PH.

The role of inhaled NO in vasoreactivity testing and therapeutic uses of this agent in adults are discussed in this topic review. The use of inhaled NO in the management of infants with persistent PH and the role of exhaled NO as a marker of disease activity in asthma and other chronic lung diseases are discussed separately. (See "Persistent pulmonary hypertension of the newborn", section on 'Inhaled nitric oxide' and "Exhaled nitric oxide analysis and applications".)

BIOLOGY AND PHARMACOKINETICS

Endogenous nitric oxide (NO) is produced from L-arginine in vascular endothelial cells by endothelial nitric oxide synthase (eNOS, type III NOS), a constitutively expressed enzyme [2]. With the help of several key cofactors, NOS catalyzes a multi-step reaction in which L-arginine and oxygen are converted to L-citrulline and NO. NO that is synthesized by vascular endothelial cells diffuses into adjacent vascular smooth muscle and decreases vascular tone in the systemic and pulmonary circulation [3,4]. When administered by inhalation, it selectively dilates pulmonary vasculature in ventilated areas of the lung. The vasodilating effect of inhaled NO has a rapid onset of action and a short half-life that results in essentially no effect on systemic vessels making it a highly selective, short acting pulmonary vasodilator and an ideal agent for pulmonary vasoreactivity testing. (See 'Vasoreactivity testing' below.)

Mechanism of action – NO activates soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), which then activates cGMP dependent protein kinase (PKG) which results in the activation of several regulatory mechanisms that decrease intracellular calcium and decrease vascular smooth muscle tone (ie, vasodilation) in precapillary resistance arterioles [2,5]. Additional effects of NO include suppression of both smooth muscle proliferation and platelet aggregation [6,7].

These properties have led to the development of inhaled NO and other agents that enhance the NO/cGMP signaling pathway such as sildenafil and tadalafil (phosphodiesterase type-5 [PDE5] inhibitors), or riociguat, an sGC stimulator. Inhaled NO has been shown to be effective at reducing pulmonary vascular resistance at doses as low as 1 part per million (ppm). A vasodilator effect of NO has been demonstrated with as little as 0.1 ppm and there appears to be a threshold for pulmonary vasodilation that occurs at a dose of approximately 10 ppm [8-10]. Administration of inhaled NO is discussed below. (See 'Procedure' below.)

            
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Literature review current through: Sep 2017. | This topic last updated: Aug 08, 2017.
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