**1. Introduction**

All conditions causing pulmonary hypertension (PH) are characterized by three major changes in the pulmonary vasculature: vasoconstriction, vascular remodeling, and thrombosis [1,2,3]. Vascular remodeling includes muscularization of normally non-muscular peripheral pulmo‐ nary arteries, increase in medial wall thickness of muscular arteries, and increase in vascular connective tissue such as collagen and elastin [1,2,3]. Imbalance of vasoconstrictive and vasodilatory mediators might explain the increased vascular tone [1,2,3]. Endothelial cells synthesize and release prostacylin and nitric oxide for vasodilation as well as endothelin and thromboxane for vasoconstriction. Approved treatments for pulmonary arterial hypertension (PAH) include prostacyclins, endothelin receptor blockers, and phosphodiesterase-5 inhibitors as well as inhaled NO for persistent pulmonary hypertension of the neonate (PPHN) [2].

Studies have demonstrated that short- and long-term NO inhalation improves arterial oxygenation and reduces pulmonary artery (PA) pressure in animal models of PH [4,5,6,7,8,9,10] and clinical disease such as post-operative congenital heart disease [11,12], chronic obstructive pulmonary disease (COPD) [13], pulmonary fibrosis [14], and acute respiratory distress syndrome (ARDS) [15]. In chronic hypoxia-induced PH in rats, we showed that low-dose NO (less than 5ppm) induces a submaximal reduction in pulmonary artery pressure, which does not correlate with the severity of pulmonary vascular changes [4]. Clinically, the effect of inhaled NO is based on pulmonary vasorelaxation. In experimental settings, NO inhibits vascular smooth muscle cell proliferation directly through regulating protein kinases modulating gene expression for cell growth and/or indirectly through reducing pressure on the vascular cells by cyclic guanosine-3',5'-monophosphate (cGMP) dependent

© 2013 Maruyama et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Maruyama et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

vascular relaxation. In this chapter we will discuss NO and its regulation and function with special references to the development of PH as well as pulmonary vascular reactivity in PH.

nary pressures precedes the vascular structural changes in chronic hypoxia-induced PH, whereas the reverse sequence of events occurs in MCT-induced PH. Endogenous NO from Larginine could prevent the development of new muscularization of peripheral pulmonary arteries in both models, whereas exogenous inhaled NO would be effective only in hypoxiainduced PH because of the reduction in pulmonary vascular pressures caused by NO mediated

Nitric Oxide in Pathophysiology and Treatment of Pulmonary Hypertension

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Inhaled NO likely attenuates the hypertensive vascular structural changes through pulmonary vasodilation by a cGMP-mediated mechanism. Endogenous NO from L-arginine might also prevent the development of structural changes through a cGMP-mediated mechanism. This hypothesis is supported by another study that showed that pulmonary gene transfection of atrial natriuretic peptide (ANP), another inducer of cGMP, attenuates the development of chronic hypoxia-induced pulmonary vascular changes [25]. Treatment to increase NO production in the pulmonary vascular bed by eNOS gene transfection ameliorates the development of PH. Studies have demonstrated that eNOS transfected smooth muscle cell administration prevented the development of MCT-induced PH [26] and that eNOS trans‐ fected bone marrow-derived endothelial-like progenitor cell venous administration reversed

**) as sources of NO (Figure 1)**

), can be recycled to NO in vivo as alternative

NO is produced from L-arginine by nitric oxide synthase (NOS) in the presence of oxygen, tetrahydrobiopterin (BH4), and reduced NADPH[3]. Recent studies have indicated that

sources of NO in addition to the classical NOS-NO pathway. The source of nitrate includes the endogenous NOS-NO synthase pathway and the diet. Green vegetables such as lettuce and spinach provide nitrate and preservatives in cured meat and bacon include nitrite. Basically reduction of nitrate and nitrite produce NO, thus nitrate and nitrite are considered an 'endo‐

Nitrate in the plasma is excreted into the saliva, whereas nitrate is reduced by the oral anerobic bacteria producing nitrite. These bacteria use nitrate as an electron acceptor instead of oxygen during respiration. During its subsequent movement into the stomach, nitrite undergoes further reduction to NO, thus leading to gastric NO formation, which may play a role in gastric mucosa maintenance. This is a entro-salivary circulation of nitrate. In the systemic circulation intravascular nitrite is reduced to NO by deoxyHb, respiratory chain enzymes, xanthine oxidoreductase, deoxygenated myoglobin, and protons ( 29 ). They facilitate the transfer of

Nitrite has a vasodilatory effect. Inhaled nebulized sodium nitrite reduces pulmonary artery pressure (PAP) without changes in systemic artery pressure in hypoxia- or thromboxane-

, causing NO production which is intensified under acidic and hypoxic states.


vasodilation.

established MCT-induced PH [27].

**3. Endogenous NO production**

**) and nitrite (NO2**


**-**

) and nitrite (NO2

**-**

inorganic anions, nitrate (NO3

crine reservoir' of NO [28].


Artery-to-vein gradients in nitrite are observed.

protons to NO2

**3.1. Nitrate (NO3**
