The mechanical load imposed by the parenchyma can decrease the magnitude of agonist-induced airway constriction. To examine whether variability in mechanical interdependence could account for differences in airway narrowing among different species, we compared the effects of changing lung volume on airway resistance (Raw) under baseline conditions and during methacholine (MCh)-induced constriction in rats and guinea pigs. Direct measurements of Raw were made under baseline conditions at different levels of end-expiratory transpulmonary pressure (PL = 3-11 cmH2O). Then aerosolized MCh was delivered (128 mg/ml in rats, 8 mg/ml in guinea pigs), and measurements were obtained at different levels of PL (3-11 cmH2O). We measured tracheal flow and tracheal and alveolar pressure (using alveolar capsules) in open-chest animals during mechanical ventilation (tidal volume 6 ml/kg, frequency 1 Hz) and calculated Raw by subtracting tissue from total lung resistance. For interspecies comparisons, data were standardized using percent change in Raw (delta % Raw) at PL of 3 cmH2O during baseline and, after MCh, log-scaled delta % Raw at PL of 3 cmH2O. We found that increasing lung volume decreased Raw both at baseline and after MCh in both species. However, changes were far smaller in guinea pigs. During baseline, the slope of the delta % Raw/delta PL was -3.37 and -12.48 %/cmH2O for guinea pigs and rats, respectively (P < 0.001). After MCh, the slope of delta log %Raw/delta PL was -0.065 and -0.154 cmH2O-1 for guinea pigs and rats, respectively (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)