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

Abstract

Inhaled-nitric oxide (NO) is a selective pulmonary vasodilator in shortterm 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 µL·h -1 ). Pulmonary haemodynamics 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. Eur Respir J., 1996Respir J., , 9, 1475 The study was supported by the American Heart Association-Minnesota Affiliate GrantIn-Aid, US Department of Veterans Affairs, Minnesota Medical Foundation, and the National Institutes of Health Grant #1R29-HL45735.Pulmonary hypertension is a leading cause of morbidity and mortality in association with chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), or congenital heart disease, and as a primary disorder [1]. Nitric oxide (NO) is a potent pulmonary vasodilator [2][3][4]. When inhaled, NO selectively dilates the pulmonary vasculature [3,4]. In situations requiring acute and subacute treatment, such as neonatal pulmonary hypertensive crisis or ARDS, inhaled NO is highly effective in reducing pulmonary hypertension [5][6][7][8]. In these situations, the patient is typically intubated and continuously attended by specially trained medical staff, and the duration of the treatment is relatively short. The usefulness of inhaled NO in chronic diseases, such as COPD, has not been systematically clinically tested, partly due to fears of NO toxicity, and particularly due to technical difficulties related to the ambulatory delivery of inhaled NO gas. Nevertheless, the ability of long-term NO inhalation to reduce chronic hypoxic pulmonary hypertension and related right ventricular hypertrophy has been demonstrated in adult and neonatal rats [9,10].Chronic NO inhalation in humans would require very strict sa...

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