Chronic infusion of nitric oxide in experimental pulmonary hypertension: pulmonary pressure-flow analysis

Inhaled-nitric oxide (NO) is a selective pulmonary vasodilator in short-term clinical studies. Use of NO inhalation in chronic pulmonary hypertension is complicated by potential problems with ambulatory NO delivery. We hypothesized that long-term infusion of NO solution into the central venous circulation, which did not suffer from this drawback, might reduce chronic pulmonary hypertension. Saturated NO solution was infused in chronically hypoxic rats by implantable minipumps at a rate which was effective in reducing acute hypoxic vasoconstriction in isolated, Krebs' albumin perfused lungs (2.5 microL.h-1). Pulmonary haemo dynamics and the pressure-flow relationship were studied after 4 weeks of infusion. NO was still present in the minipumps at the end of the infusion period. Despite causing methaemoglobinaemia, NO infusion did not significantly attenuate pulmonary arterial pressure, pulmonary vascular resistance, right ventricular hypertrophy, or the parameters of the pulmonary vascular pressure-flow relationship. Pressure-flow curves, analysed with the nonlinear, distensible vessel model, indicated increased near-zero pressure resistance (Ro) in chronic hypoxia. The tendency of chronic NO infusion to reduce Ro did not reach statistical significance. Long-term infusion of nitric oxide solution is technically feasible but does not effectively reverse chronic pulmonary hypertension. The failure of infused NO to reduce pulmonary hypertension is explained by the fact that the inactivation of NO by haemoglobin is much faster than anticipated.