Ischaemic preconditioning of the lung leads to a protective effect against ischaemia-reperfusion injury, but the underlying mechanisms of this protection are not well documented in the lung. The aim of this study was to investigate the role of endogenous and exogenous peroxynitrite (ONOO-) in preconditioning of isolated rat lungs. Lungs, obtained from male rats, were mounted on a perfusion apparatus, perfused by Krebs-Henseleit solution at the rate of 0.03 ml g(-1) min(-1) and inflated with room air. Pulmonary perfusion pressure was measured by a pressure transducer and recorded continuously on a computer by using data acquisition system. Lungs were preconditioned for 5 min by either ischaemia or ONOO- administration at 10 mu M, which were followed by 5 min reperfusion and 2h of ischaemia and 10 min reperfusion. Two hours of ischaerma without preconditioning depressed potassium chloride (KCI)-and phenylephrine hydrochloride (PE)-induced responses. Pretreatment of the lungs with ONOO- scavenger, uric acid (1mM), or poly ADP-ribose synthase inhibitors, 3-aminobenzamid (3-AB, 1mM) or nicotinamide (1mM), reversed the effects ischaemia and ONOO--induced preconditioning and decreased KCI- and PE-induced increases in perfusion pressures. Wet/dry weight ratio was markedly reduced in ischaemia and ONOO--induced preconditioning groups indicating that preconditioning prevents lung oedema. Lung malondialdehyde (MDA) levels were significantly depressed in ischaemic and ONOO- preconditioning groups. These results suggest that ONOO- is able to precondition the isolated rat lung and plays a significant role in the protective effects of preconditioning. (c) 2006 Elsevier Ltd. All rights reserved.