We measured the change in total lung resistance (RL) and that in total lung elastance (EL) induced by hypoxia (n = 7) and compared the results with those by intravenous histamine bolus (n = 5) at three different positive end-expiratory pressure (PEEP) levels (2, 5, and 8 hPa) in open-chest and vagotomized rabbits. The percent increase ratio of RL (PIRR) and EL (PIRE) was defined as the change in RL and EL, respectively, induced by hypoxia compared with that in the normoxic condition, expressed as a percentage. PIR values for the change in RL and EL induced by bolus injection of histamine were also calculated. The PIRR and PIRE induced by hypoxia and by histamine were positive by a statistically significant amount at every PEEP level, except for the PIRE value at 8-hPa PEEP in the hypoxic challenge. The PIRE-to-PIRR ratio values in the hypoxic challenge at 2-hPa PEEP were significantly larger than those in the histamine challenge (hypoxia: 0.91 +/- 0.23%; histamine: 0.37 +/- 0. 065%, P < 0.05). The increase in EL induced by histamine in the acute phase has been reported to be mainly derived from tissue distortion secondary to bronchial constriction. Thus our results suggest that a part of the increase in EL by hypoxia was originated in different parenchymal responses from histamine and imply that this hypoxic response of lung parenchyma is sensitive to the increase in parenchymal tethering at high PEEP levels.