Despite the therapeutic importance of propranolol and the potential usefulness of propranolol extraction measurements for the assessment of lung disorders, the pulmonary disposition of propranolol remains poorly understood. The extraction, accumulation and distribution of propranolol in lungs of conscious and anesthetized sheep were investigated by indicator-dilution methods, lung lymph fistula preparations and bronchoalveolar lavage. Pulmonary extraction of propranolol from plasma (0.81 +/- 0.03) was significantly less than that of imipramine (0.89 +/- 0.03), not significantly different from that of lidocaine (0.74 +/- 0.03) and much greater than that of water (0.44 +/- 0.02), whereas there were no differences in apparent red blood cell extraction of each indicator from plasma in vitro as determined under similar conditions (0.08-0.1). Pulmonary accumulation of imipramine (78 +/- 3%), lidocaine (52 +/- 4%), propranolol (37 +/- 4%) and water (7 +/- 2%), after a single pass through the pulmonary circulation, correlated positively with octanol/saline partition coefficients but not with pKa values. After bolus i.v. injection of [3H]propranolol, tritium concentrations in lung lymph increased rapidly to exceed plasma concentrations within 60 min and tritium concentrations in bronchoalveolar lavage equaled plasma concentrations 5 to 15 min after injection. It is concluded that by a mechanism not involving molecular charge, propranolol permeates capillary endothelium and alveolar epithelium to accumulate in hydrophobic regions of the lungs. This study in normal sheep suggests that reduced propranolol extraction by damaged lungs reflects pathological alterations other than endothelial cell dysfunction, such as pulmonary edema.