This study tested the hypothesis that in the awake sheep, airway responsiveness to aerosol histamine would be increased acutely by endotoxemia. Eleven sheep were chronically instrumented to allow for measurements of lung lymph flow, vascular pressures, and lung mechanics. Awake sheep were studied in a whole-body plethysmograph designed to measure dynamic compliance (Cdyn), resistance of the lung (RL), and functional residual capacity (FRC). Pulmonary responsiveness to aerosol histamine was assessed by giving five breaths of increasing concentrations of histamine (0.1-50 mg/ml) until Cdyn decreased to 65% (of control) or until 50 mg/ml of histamine had been given. Escherichia coli endotoxin (0.2-0.5 microgram/kg) was then infused, and at 5 h after endotoxemia pulmonary responsiveness to aerosol histamine was remeasured. After endotoxin, 9 of the 11 sheep exhibited decreased Cdyn at a lower concentration of histamine compared with the preendotoxin level (P less than 0.05). The mean of the log dose of histamine necessary to reduce Cdyn to 65% of control was 1.00 +/- 0.16 (SE) before endotoxin and 0.027 +/- 0.29 5 h after endotoxin; i.e., histamine responsiveness was increased. In the last 3 sheep studied, atropine (0.1 mg/kg iv) was given after the second aerosol histamine challenge, and a third dose-response curve was performed. Atropine did not return the endotoxin-induced increase in histamine responsiveness to base line. There was no correlation between the change in histamine responsiveness and the endotoxin-induced changes in Cdyn, FRC, RL, alveolar-arterial O2 difference, pulmonary arterial pressure, or lung lymph flow.