Acute hypoxic pulmonary vasoconstriction is an adaptive response that optimizes the ratio of alveolar ventilation to regional pulmonary perfusion thereby improving oxygen uptake. However, sustained exposure to hypoxia produces a chronic hypoxic vasoconstriction, which is no longer immediately reversible with correction of alveolar hypoxia. Thus, the vasoconstriction in chronically hypoxic hypertensive lungs is distinct from acute hypoxic pulmonary vasoconstriction. This chronic hypoxic vasoconstriction is associated with the development of pulmonary artery hypertension and right ventricular strain. We recently demonstrated that Rho-A/Rho-Kinase inhibition returns pulmonary artery pressures to near normal values in chronically hypertensive lungs [1]. While inhibition of the Rho-A/Rho-Kinase pathway reverses much of the chronic hypoxic vasoconstriction, it is unknown if chronic hypoxic vasoconstriction has a role in V/Q matching in the lung. Adult male rats (n=6 per group) were housed in a normobaric hypoxic chamber (FiO2 0.10) for 3 weeks. Anaesthesia was induced with pentobarbitone (60mg/kg, i.p.), venous and arterial cannulae were placed for drug administration, blood gas sampling, heart rate and blood pressure monitoring. Adequate depth of anaesthesia maintained with Saffan (Alfaxalone 0.3% and Alfadalone 0.1%,0.1-2 ml/h i.v.) and monitored throughout the experiment by the haemodynamic response to paw pinch. A tracheostomy was performed and mechanical ventilation (FiO2 0.3) was commenced after neuromuscular blockade with pancuronium (2mg i.v.). The rats were allowed to stabilise and arterial blood gas measurements were then made 30 min before and after i.v. administration of the Rho-Kinase inhibitor Y-27632 (15mg/kg, i.v.) as previously described [1] or vehicle. Animals were humanely killed at the end of the experiments. The (mean±S.E.M.) alveolar-arterial oxygen (A-aO2) gap was not significantly different (p=0.56, t test) following the administration of Y-27632 (38.1±9.1mmHg) from the initial value (40.5±3.2mmHg). The partial pressure of oxygen in arterial blood (PaO2) was not significantly different (p=0.31, t test)) following the administration of Y-27632 (137.8±5.9mmHg) from the initial value (132.2±2.8mmHg). There was no difference in A-aO2 gap and PaO2 following injection of vehicle. Y-27632 caused a significant attenuation of right ventricular systolic pressure max in chronic hypoxia when compared to vehicle (p<0.01). These findings suggest that unlike acute hypoxic pulmonary vasoconstriction, chronic hypoxic pulmonary vasoconstriction is not important in maintaining arterial oxygenation. Reversal of the chronic hypoxic vasoconstriction does not alter the A-aO2 gap in the lung. These results support the view that chronic hypoxic vasoconstriction is a maladaptive response which overloads the right ventricle with no obvious benefit to gas exchange.