NEBULIZED NITRIC-OXIDE NUCLEOPHILE ADDUCT REDUCES CHRONIC PULMONARY-HYPERTENSION

Objective: Inhaled nitric oxide (NO) is a selective pulmonary vasodila tor, but its use has been restricted almost exclusively to the intensi ve care setting due to the complexity of its delivery. NO/nucleophile adducts, such as diethylenetriamine/NO (DETA/NO), spontaneously releas e NO in aqueous solutions. We hypothesized that a nebulized DETA/NO (h alf-time of NO release > 20 h) would stay in the lower airways and con tinuously supply sufficient NO to achieve sustained vasodilation in ch ronic pulmonary hypertension. Methods: Chronic pulmonary hypertension was induced in rats by a monocrotaline injection, Nineteen days later, nebulizations of DETA/NO were given on 4 consecutive days (5 and 50 m u mol; 10 min/day). One day after the last nebulization, pulmonary and systemic arterial pressure and cardiac output were measured after tho racotomy. The lungs were isolated and perfused to study the pressure-f low relationship. The effect of DETA/NO nebulization on acute vasocons trictor reactivity was studied in additional isolated lungs. Results: Total pulmonary, but not systemic, vascular resistance was significant ly reduced by both DETA/NO doses, suggesting that DETA/NO, like NO, ca uses preferential dilation of the pulmonary circulation. The pulmonary perfusion pressure-flow curves were shifted downwards by DETA/NO trea tment, indicating improved resistive properties of the pulmonary vascu lature. DETA/NO nebulization into isolated lungs increased exhaled NO levels and progressively reduced vasoconstrictor responses to angioten sin II and acute hypoxia. These effects were not reversed by perfusate exchange, In intact rats, carotid artery pressure and plasma NO2- + N O3- levels did not change during and after DETA/NO nebulization. Concl usion: DETA/NO nebulization offers a possibility of once a day, ambula tory delivery of NO and is a potential treatment for chronic pulmonary hypertension, although further studies are needed to establish safely and selectivity.