The intrapulmonary mechanism by which airway hypoxia causes pulmonary arterial constriction is poorly understood. It is generally believed that hypoxia either elicits the release of a chemical mediator from the lung parenchyma or has a direct excitatory effect on the smooth muscle of the peripheral pulmonary arteries. We are testing the working hypothesis that hypoxia acts directly on the vascular smooth muscle to depress the rate of mitochondrial oxidative phosphorylation and to cause shifts in cytoplasmic metabolite concentrations, which then lead to membrane depolarization, calcium influx, and contraction. Results from studies of isolated perfused rat lungs with pharmacologic inhibitors of oxidative phosphorylation, glycolysis, and calcium influx have provided indirect support for the hypothesis; but a simpler in vitro preparation allowing direct measurements of energy metabolism, membrane electrical activity, calcium fluxes, and muscle tone is needed. Additional experiments have shown that inhibitors of membrane K+ conductance allow hypoxic contractions of isolated vascular smooth muscle; and such a preparation might be useful as an in vitro model of hypoxic pulmonary vasoconstriction.