Inhaled vasodilators as a new treatment strategy in pulmonary hypertension with left heart disease

Patients with congestive heart failure (CHF) develop pulmonary hypertension due to an increase in pulmonary vascular resistance (PVR). These patients may benefit from inhaled vasodilators to selectively reduce PVR. Here, we studied the effects of inhaled vasodilators on pulmonary and systemic hemodynamics and lung edema formation in a rat model of CHF. Since lungs of CHF patients are partially protected from lung edema formation, we further investigated the effect of CHF on alveolar fluid reabsorption and its regulation by endothelial-derived nitric oxide (NO). CHF was induced by aortic banding in rats. Pulmonary hemodynamics and edema formation were analyzed in vivo after inhalation of the vasodilators milrinone, iloprost or NO at rest, and inhaled iloprost at increased lung perfusion after administration of the β1-agonist dobutamine. Alveolar fluid reabsorption and endothelial NO production in CHF were quantified in the isolated perfused rat lung by double indicator dilution technique and by fluorescence imaging of pulmonary endothelial cells in situ. Inhalation of milrinone, iloprost, or NO reduced pulmonary arterial pressure (PAP), PVR and the ratio of PVR over the systemic vascular resistance (SVR). Repetitive inhalation of milrinone or iloprost, or continuous inhalation of NO, respectively, caused prolonged pulmonary vasodilation, with milrinone and iloprost being superior to NO. At rest, inhaled vasodilators neither caused lung edema nor left ventricular overload, yet at increased lung perfusion inhaled iloprost promoted lung edema formation in CHF rats. This increase in lung edema was attributable to an inhibition of the Kitajew reflex which postulates a vasoconstriction of precapillary sphincters to protect the pulmonary capillary bed from excessive hydrostatic pressures. Rats with chronic CHF had a markedly increased alveolar fluid reabsorption at elevated left atrial pressure (PLA). This protective effect was attributable to a reduced endothelial NO production in CHF. These results demonstrate that inhaled vasodilators selectively reduce PVR and decrease right ventricular afterload in CHF. While an increased alveolar fluid reabsorption in CHF protects the lung from edema at rest, inhalation of vasodilators at increased perfusion may cause lung edema due to an inhibition of the Kitajew reflex.