A Novel Inhaled Organic Nitrate That Affects Pulmonary Vascular Tone in a Piglet Model of Hypoxia-Induced Pulmonary Hypertension

Abstract

Persistent pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance after birth leading to right-to-left shunting and systemic arterial hypoxemia. Inhaled nitric oxide (NO) is effective in reducing the need for extracorporeal membrane oxygenation, but it has potential toxicities, especially in an oxygen-rich environment. A number of other NO-based molecules have been given by inhalation, but their structure-function relationships have not been established. Recent studies have raised the idea that toxic and beneficial properties can be separated. We synthesized a novel organic nitrate [ethyl nitrate (ENO 2 )], tested it in vitro, and administered it to hypoxic piglets. ENO 2 lowered pulmonary artery pressure and raised the PO 2 in arterial blood but did not alter systemic vascular resistance or methemoglobin levels. In addition, we tested the effect of ENO 2 in the presence of the thiol glutathione, both in vivo and in vitro, and found its action to be enhanced. Although ENO 2 is less potent than inhaled NO on a doseequivalency basis, pretreatment of hypoxic animals with glutathione, which may be depleted in injured lungs, led to a markedly enhanced effect (largely mitigating the difference in potency). The disease entity persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR) after birth leading to extrapulmonary right-to-left shunting through the patent foramen ovale and patent ductus arteriosus with resulting systemic arterial hypoxemia. These patients are frequently treated with inhaled nitric oxide (NO) and may require extracorporeal membrane oxygenation; those with severe respiratory failure are at increased risk for neurodevelopmental impairment (1,2). NO's clinical effectiveness has been well documented (3-6), although some reports suggest that it may exacerbate lung inflammation (7), raising the concern that it may have toxic properties in some clinical settings. Infants who receive inhaled NO for PPHN are often treated with high inspired oxygen, and in the O 2 -rich environment of the lung, higher oxides of nitrogen (NO x ) including peroxynitrite may form (8), which can cause hemorrhage, inflammation, and edema (9,10). Airways of animal and human subjects who have received inhaled NO showed the same patterns of oxidative injury found in animals and humans who were exposed to NO x or hyperoxia (11,12).Inhaled, exogenous NO is delivered to well-ventilated parts of the lung and will stimulate guanylate cyclase activity, leading to vascular smooth muscle relaxation. Thus, NO has been effective in lowering pulmonary artery pressure (PAP)

Interactions of Cardiopulmonary Bypass and Erythrocyte Transfusion in the Pathogenesis of Pulmonary Dysfunction in Swine

“…Swine are excellent models of respiratory disease as anatomy, biochemistry, physiology, size, and genetics resemble those of humans. 19 As a result, porcine lungs have been used to study many respiratory diseases and therapeutics, including surfactant function and therapy, 20 reperfusion injury, 21 pulmonary artery hypertension, 22 and the effects of mechanical ventilation. 17 Importantly, our results are comparable with a recent clinical study in which healthy volunteers when transfused with autologous blood developed subclinical pulmonary dysfunction associated with increases in markers of pulmonary inflammation.…”

Nitric Oxide in the Pulmonary Vasculature

“…88 ENO 2 was shown to lower pulmonary artery pressure and PVR selectively in a model of hypoxia-induced PH, without significant systemic effect. 89 Although ENO 2 alone has a potency 100-fold lower than iNO, the addition of glutathione dramatically increased its activity, presumably by enhancing the formation of SNOs.…”

The porcine lung as a potential model for cystic fibrosis

“…The swine lung has become an excellent model for the normal human lung, for abnormalities in diseases, and for therapeutics. For example, porcine lungs have been used to study surfactant composition (215), surfactant function and therapy (101), lung development (82), lung transplantation, perfluorocarbon liquid ventilation (57), reperfusion injury (34), nitrous oxide effects on lung function (203), hyperoxia-induced and other toxin-induced lung injuries (89), pulmonary artery hypertension (24), endothelin and growth factor receptor biology (227), lung growth after lobectomy (125), bronchiolitis obliterans (2), effects of mechanical ventilatory modes (143), airway hyperresponsiveness (161), asthma (119), and many other diseases. Pigs have been employed to evaluate viral and nonviral vector-mediated gene transfer to the lung (48,151,162).…”