Nitric oxide in paediatric respiratory disorders: novel interventions to address associated vascular phenomena?

Abstract

Nitric oxide (NO) has a significant role in modulating the respiratory system and is being exploited therapeutically. Neonatal respiratory failure can affect around 2% of all live births and is responsible for over one third of all neonatal mortality. Current treatment method with inhaled NO (iNO) has demonstrated great benefits to patients with persistent pulmonary hypertension, bronchopulmonary dysplasia and neonatal respiratory distress syndrome. However, it is not without its drawbacks, which include the need for patients to be attached to mechanical ventilators. Notably, there is also a lack of identification of subgroups amongst abovementioned patients, and homogeneity in powered studies associated with iNO, which is one of the limitations. There are significant developments in drug delivery methods and there is a need to look at alternative or supplementary methods of NO delivery that could reduce current concerns. The addition of NO-independent activators and stimulators, or drugs such as prostaglandins to work in synergy with NO donors might be beneficial. It is of interest to consider such delivery methods within the respiratory system, where controlled release of NO can be introduced whilst minimizing the production of harmful byproducts. This article reviews current therapeutic application of iNO and the state-of-the-art technology methods for sustained delivery of NO that may be adapted and developed to address respiratory disorders. We envisage this perspective would prompt active investigation of such systems for their potential clinical benefit.

Keywords: inhaled nitric oxide; nitric oxide; pulmonary; respiratory; vascular.

Figure 1.

Schematic of the action of inhaled nitric oxide (iNO) in the lung leading to improved ventilation–perfusion matching (central image) and the mechanism underlying vasodilatation (top right). (A) Vasoconstriction of pulmonary bed with normal and atelectatic alveoli. (B) The nitric oxide (NO) donor causes nonselective vasodilation of all pulmonary arteries, which may worsen ventilation–perfusion (V/Q) matching. (C) iNO dilates only ventilated alveoli, an outcome that improves V/Q matching. [From: Lunn, R. (1995) Subspecialty clinics: anesthesiology; inhaled nitric oxide therapy. Mayo Clin Proc 70: 247–255; with permission].

Figure 2.

Nitric oxide release systems. The main categories of nitric oxide (NO)-eluting systems currently employed for pulmonary delivery of NO; detailed studies are summarized in Table 1. Polymers: Polymers loaded with NO have been created that can be delivered into aerosol formulations and delivered to the pulmonary system [Smith and Serhatkulu, 2001]. Microparticles: Microspheres are small spherical microparticles consisting of natural and synthetic polymers with sizes in range from 1 μm to 1000 μm. The released NO induces the cyclic guanosine monophosphate signalling pathway, thus causes vasorelaxation [Yoo et al. 2010]. Nanoparticles: Several nanoparticle-based delivery systems have been developed for administration by the pulmonary route.

Figure 3.

Classes of nitric oxide (NO) donors and soluble guanylate cyclase (sGC) activators and stimulators. (A) The 4 main classes of NO donors: Diazeniumdiolates generate NO in a highly predictable manner. S-nitrosothiols do not spontaneously release NO, may decompose under certain conditions. Nitrobenzenes have been shown to be an effective NO donor for photo-controllable release [Horinouchi et al. 2011]. (B) sGC stimulators: Bayers group in 1994 discovered NO independent sGC stimulators. Researchers at Taiwan reported characterized a compound named YC-1 as a direct NO-independent, but haem-dependent sGC stimulator [Ko et al. 1994]. Further studies to improve potency and specificity of this class of drugs were developed with BAY 41-2272 and BAY 41-8543 [Stasch et al. 2001, 2002]. Riociguat is the first sGC stimulator to be used in clinical studies in patients. (C) sGC activators: Cinaciguat (BAY-58-2667) activates sGC in its oxidized or haem-free state, when the enzyme is insensitive to both NO and nitro-vasodilators [Tamargo et al. 2010].

Figure 4.

Current commercially available tracheal stents. (A) Silicone stents come in basic cylindrical shapes for placement above the carina and Y-shaped stents for placement in the distal trachea, carina and proximal bronchi. They are well tolerated and suitable for long-term placement and have a flexible material with stud designs, allowing fixation between the cartilaginous rings of the trachea that prevents migration of the stents. However, they commonly suffer from obstruction due to build up of mucous, and reactionary granulation can occur at the proximal and distal ends. (B) Metal stents: Tracheal stents can also be made of expandable and bioabsorbable metal. These have thinner walls, are more easily inserted and have fewer tendencies to trap secretions [Hsia and Musani, 2011].

Figure 5.

Nitric oxide (NO)-releasing implant in the trachea for paediatric respiratory diseases. (A) NO released from the stent is carried to the alveoli. The NO acts via the cGMP pathway, causing vasorelaxation. It then diffuses out of the pulmonary vasculature and becomes inactivated in the systemic vasculature once bound to haemoglobin. (B) NO delivery to the respiratory system has been widely explored. Several advantages make the lung an efficient route for NO delivery including a large absorptive surface area. Inhalation of NO gas leads to direct delivery to the desired site. It can redirect blood flow from poorly aerated areas to better-ventilated areas and improve ventilation perfusion mismatch. In comparison, intravenous vasodilators lack selectivity, resulting in a decrease in systemic arterial pressure and increase intrapulmonary shunt [Bernasconi and Beghetti, 2002].