Nebulized nitric oxide/nucleophile adduct reduces chronic pulmonary hypertension

Abstract

Inhaled nitric oxide (NO) is a selective pulmonary vasodilator, but its use has been restricted almost exclusively to the intensive care setting due to the complexity of its delivery. NO/nucleophile adducts, such as diethylenetriamine/NO (DETA/NO), spontaneously release NO in aqueous solutions. We hypothesized that a nebulized DETA/NO (half-time of NO release > 20 h) would stay in the lower airways and continuously supply sufficient NO to achieve sustained vasodilation in chronic pulmonary hypertension. 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 mu mol; 10 min/day). One day after the last nebulization, pulmonary and systemic arterial pressure and cardiac output were measured after thoracotomy. The lungs were isolated and perfused to study the pressure-flow relationship. The effect of DETA/NO nebulization on acute vasoconstrictor reactivity was studied in additional isolated lungs. Total pulmonary, but not systemic, vascular resistance was significantly reduced by both DETA/NO doses, suggesting that DETA/NO, like NO, causes preferential dilation of the pulmonary circulation. The pulmonary perfusion pressure-flow curves were shifted downwards by DETA/NO treatment, indicating improved resistive properties of the pulmonary vasculature. DETA/NO nebulization into isolated lungs increased exhaled NO levels and progressively reduced vasoconstrictor responses to angiotensin II and acute hypoxia. These effects were not reversed by perfusate exchange. In intact rats, carotid artery pressure and plasma NO2- + NO3- levels did not change during and after DETA/NO nebulization. DETA/NO nebulization offers a possibility of once a day, ambulatory delivery of NO and is a potential treatment for chronic pulmonary hypertension, although further studies are needed to establish safety and selectivity.