Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension

Chronic pulmonary hypertension is a serious complication of a number of chr onic lung and heart diseases. In addition to vasoconstriction, its pathogen esis includes injury to the peripheral pulmonary arteries leading to their structural remodeling. Increased pulmonary vascular synthesis of an endogen ous vasodilator, nitric oxide (NO), opposes excessive increases of intravas cular pressure during acute pulmonary vasoconstriction and chronic pulmonar y hypertension, although evidence for reduced NO activity in pulmonary hype rtension has also been presented. NO can modulate the degree of vascular in jury and subsequent fibroproduction, which both underlie the development of chronic pulmonary hypertension. On one hand, NO can interrupt vascular wal l injury by oxygen radicals produced in increased amounts in pulmonary hype rtension. NO can also inhibit pulmonary vascular smooth muscle and fibrobla st proliferative response to the injury. On the other hand, NO may combine with oxygen radicals to yield peroxynitrite and other related, highly react ive compounds. The oxidants formed in this manner may exert cytotoxic and c ollagenolytic effects and, therefore, promote the process of reparative vas cular remodeling. The balance between the protective and adverse effects of NO is determined by the relative amounts of NO and reactive oxygen species . We speculate that this balance may be shifted toward more severe injury e specially during exacerbations of chronic diseases associated with pulmonar y hypertension. Targeting these adverse effects of NO-derived radicals on v ascular structure represents a potential novel therapeutic approach to pulm onary hypertension in chronic lung diseases.