NO synthase isoforms are involved in the LPS-induced alteration of hypoxic vasoconstriction

Background: Acute lung injury (ALI), is clinically characterized by diffuse pulmonary infiltrates, severe hypoxemia, and disturbed control of vascular tone. Augmentation as well as attenuation of hypoxic pulmonary vasoconstriction (HPV) has been described in ALI. To better understand the potential role of iNOS and eNOS in this pathological process we used a rabbit model of LPS-induced alteration of hypoxic vasoconstriction combined with exposure to periodic hypoxia. Methods: In the model of isolated perfused rabbit lung we performed repetitive hypoxic maneuvers with 3% O 2 (10min) interrupted by 15min of normoxic ventilation. After a first control maneuver we applied a) selective iNOS inhibitors 1400W (10µM=, BYK and 191023 (1µM), b) the unselective NO synthase inhibitor L-NNA (400µM), or the NOS cofactor BH 4 (100µM) or L-arginine. Pulmonary arterial pressure (Ppa), left ventricular pressure (LVP), ventilation pressure (VP), and weight were monitored continuously. Results: LPS application induced strong augmentation of HPV with edema formation. Unselective inhibition of NOS resulted in more pronounced increase in Ppa with comparable weight gain. Different iNOS inhibitors, however, reduced the extent of Ppa increase and prevented edema formation. Interestingly, supplementation with BH 4 and L-arginine also demonstrated a partial protective effect. Conclusion: Activation of iNOS and inactivation of eNOS, possibly via uncoupling, may contribute to the modulation of HPV in LPS induced lung injury.