Inhaled Nitric Oxide

Abstract

Since the recognition of nitric oxide (NO) as a key endothelial-derived vasodilator molecule in 1987, the field of NO research has expanded to encompass many areas of biomedical research. It is now well established that NO is an important signaling molecule throughout the body. The therapeutic potential of inhaled NO as a selective pulmonary vasodilator was suggested in a lamb model of pulmonary hypertension and in patients with pulmonary hypertension in 1991. 1,2 Because NO is scavenged by hemoglobin (Hb) on diffusing into the blood and is thereby rapidly inactivated, the vasodilatory effect of inhaled NO is limited largely to the lung. This is in contrast to intravenously infused vasodilators that can cause systemic vasodilation and severe systemic arterial hypotension.Recent data indicate that inhaled NO can be applied in various diseases. For example, studies suggest that inhaled NO is a safe and effective agent to determine the vasodilatory capacity of the pulmonary vascular bed. This article summarizes the pharmacology and physiology of inhaled NO and reviews the current uses of inhaled NO for the treatment, evaluation, and prevention of cardiovascular and respiratory diseases. Pharmacology and Physiology of Inhaled NO Chemistry of NO GasNO is a colorless, odorless gas that is only slightly soluble in water. 3 NO and its oxidative byproducts (eg, NO 2 and N 2 O 4 ) are produced by the partial oxidation of atmospheric nitrogen in internal combustion engines, in the burning cinder cones of cigarettes, and in lightning storms. Medical-grade NO gas is produced under carefully controlled conditions, diluted with pure nitrogen, and stored in the absence of oxygen. The recent article by Williams 4 provides a review of the chemistry of NO. Therapeutic Versus Endogenous NO Concentrations in the AirwayAlthough early studies of inhaled NO in the treatment of pulmonary hypertension used concentrations of 5 to 80 ppm, it has since been realized that concentrations Ͼ20 ppm provide little additional hemodynamic benefit in most patients. In some adults with acute respiratory failure, the effective concentrations of inhaled NO required to improve oxygenation can be as low as 10 ppb. 5,6 Of note, NO has been detected in exhaled human breath. The majority of exhaled NO in normal humans appears to be derived from nasal bacterial flora (25 to 64 ppb), with lower concentrations measured in the mouth, trachea, and distal airway (1 to 6 ppb). 5,7 Mechanism of ActionAfter inhalation, NO diffuses rapidly across the alveolarcapillary membrane into the subjacent smooth muscle of pulmonary vessels to activate soluble guanylate cyclase (Figure 1). This enzyme mediates many of the biological effects of NO and is responsible for the conversion of GTP to cGMP. Increased intracellular concentrations of cGMP relax smooth muscle via several mechanisms. The physiological actions of cGMP are limited to its area of synthesis by its hydrolysis to GMP by cyclic nucleotide phosphodiesterases (PDE) or by its export from the cell. Of the 11 reported...

Reducing Variation in the Use of Inhaled Nitric Oxide

“…3,4 It reduces vascular tone by activating soluble guanylate cyclase, which converts guanosine triphosphate into cyclic guanosine monophosphate. Increased intracellular concentrations of cyclic guanosine monophosphate relax the smooth muscle of the pulmonary vessels.…”

Chronic pulmonary hypertension and nitric oxide

“…Положительного терапевтического эффекта уда лось добиться путем ингаляции NO (от 5 до 80 ppm), который быстро проходит через альвеолярно капил лярную мембрану в гладкую мышцу легочных сосу дов и активирует в них растворимую гуанилатцикла зу [17,18]. Достигая этим способом тока крови, NO быстро инактивируется гемоглобином, что ограни чивает его вазодилататорные эффекты только на со суды легких.…”

“…Недо статком этого метода лечения может быть риск осложнений в связи с небольшим диапазоном между концентрациями NO, вызывающими терапевтичес кий и токсический (образование метгемоглобина, двуокиси азота -NO2) эффекты. Однако при нали чии соответствующей аппаратуры, обученного пер сонала и соблюдении необходимой осторожности этих рисков можно вполне избежать [18].…”

“…Были предложены и с успехом применялись 91 http://www.pulmonology.ru Обзоры для лечения соответствующих больных различные способы нормализации уровня NO. Прежде всего это касается легочной артериальной гипертонии, тромбоэмболической легочной гипертонии, ОРДС и некоторых других.Положительного терапевтического эффекта уда лось добиться путем ингаляции NO (от 5 до 80 ppm), который быстро проходит через альвеолярно капил лярную мембрану в гладкую мышцу легочных сосу дов и активирует в них растворимую гуанилатцикла зу [17,18]. Достигая этим способом тока крови, NO быстро инактивируется гемоглобином, что ограни чивает его вазодилататорные эффекты только на со суды легких.…”

Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy

“…Inhaled NO is a useful short-term vasodilator screening agent for the identification of those patients with pulmonary arterial hypertension (PAH) who will respond to treatment with calcium channel blockers [8][9][10]. However, inhaled NO and nitrates are unsuitable as long-term treatments for pulmonary hypertension, owing to the significant numbers of nonresponding patients [11,12], the development of tolerance [13] and/or the serious problem of rebound pulmonary hypertension following discontinuation of treatment [14,15]. Targeting of a downstream component of the NO signalling pathway has met with more success; sildenafil prevents the degradation of cGMP by inhibiting phosphodiesterase (PDE)5, and has been approved for the treatment of PAH [16][17][18].…”