Chronic hypoxic pulmonary hypertension is characterized by vasoconstriction and vascular remodeling and impaired endothelial nitric oxide (NO) production. Although ischemic preconditioning of the lung leads to protective effect against ischemic reperfusion injury, the mechanisms of this protection are not well documented in the lung. The aim of this study was to investigate the effects of chronic hypoxia on preconditioning induced by ischemia or peroxynitrite in isolated rat lungs. The isolated rat lung, from exposed to hypobaric hypoxia for 21 days, was mounted on a modified Langendorff perfusion apparatus. Lungs were preconditioned by either 5 minutes' ischemia and 5 minutes' reperfusion or 10 mu M peroxynitrite prior to 2 hours of normothermic ischemia. Although ischemia-reperfusion or peroxynitrite preconditioning markedly reduced KCl responses on perfusion pressure, phenylephrine-induced responses were not significantly modified. Pretreatment of the hypoxic lungs with peroxynitrite scavenger, uric acid, or poly (ADP-ribose) synthase inhibitors (PARS), 3-aminobenzamide (3-AB) or nicotinamide, did not modify the KCl- and phenylephrine-induced responses in chronic hypoxic lungs. There were also no marked differences either in wet to dry weight ratio or malondialdehyde levels of chronic hypoxic lungs. These results imply that preconditioning does not occur in the chronic hypoxic rat lungs.