We studied the evolution of alveolar pressure (PA) heterogeneity during the course of forced expiration in the lungs of six anesthetized open-chest dogs. Using an alveolar capsule technique, we measured PA simultaneously in six lung regions during full maximal forced deflations before and after administering aerosolized histamine. Flow was measured plethysmographically with volume obtained by flow integration. Heterogeneity was expressed as the coefficient of variation (CV) of regional PA after 25% of the vital capacity had been expired from total lung capacity. The CV in in vivo open-chest canine lungs (21.3%) was significantly greater than that we measured previously in excised lungs (8.7%) (P < 0.02). Inhalation of aerosolized solutions of histamine produced significant increases in interregional heterogeneity (CV = 35.5 and 38.8% after 3 and 10 mg/ml of histamine, respectively; P < 0.025). After histamine, the vital capacity was reduced and the configuration of the flow-volume curve demonstrated some shortening of the flow plateau commonly observed in dogs. Changes in the flow-volume relationship failed, however, to reflect well the marked degree of heterogeneity of PA after histamine administration. These findings may be reconciled on the basis of interdependence of regional expiratory flows. Reductions in flow from obstructed regions appear to be compensated by increases in flow from unobstructed regions and thus mask upstream nonuniformities. These mechanisms may explain in part why the maximal expiratory flow-volume curve has been a relatively insensitive tool for the detection of early nonuniform airway disease.