This project will investigate the presence and impact of temporal variations in regional pulmonary ventilation and perfusion and the role of lung carbonic anhydrase (CA) in ventilation-perfusion (V/Q) matching. The remarkable efficiency of gas exchange in the normal lung is based upon the regional matching of ventilation and perfusion which arise from both structural (anatomic) attributes of the lung as well as active mechanisms regulating the distribution of ventilation and perfusion. Although factors affecting spatial heterogeneity in blood flow and ventilation have been studied extensively, very little is known about how temporal variations affect overall heterogeneity. The hypotheses of this investigation are that in the lung, 1) temporal fluctuations in regional blood flow and ventilation do occur, 2) they are of sufficient magnitude to contribute to V/Q mismatch, and 3) the effect is minimized by rapid compensatory changes in ventilation (in response to blood flow changes) and perfusion (in response to ventilation changes) mediated by consequent changes in local CO2 tensions. CO2 has known bronchodilator and pulmonary vasoconstrictor effects in addition to effects on the functional properties of alveolar surfactant which will act to reduce mismatching in the face of local fluctuations in ventilation and perfusion. As in most physiological systems, CO2 acts as an acid (ie CO2 + H2O equilibrium H2CO2 equilibrium H+ + HCO(-3)); thus rapid catalysis of these reactions by CA will assure that changes in regional PCO2 brought about by temporal variations in local perfusion (varying CO2 delivery) or ventilation (varying CO2 elimination) can rapidly alter pH in airway and alveolar tissue. The experimental approach will be to impose changes in the magnitude and/or CO2 content of regional perfusion and ventilation and to measure the kinetics of compensatory readjustments before and after inhibition of lung CA in a variety of experimental protocols in animals and humans. In addition, the spontaneous temporal variability in regional lung perfusion, ventilation and V/Q will be quantified by positron emission tomography. These studies will define a new role for lung carbonic anhydrase in pulmonary gas exchange and provide further insights into the problems associated with the clinical use of carbonic anhydrase inhibitors, especially in those patients with underlying lung disease, in whom the loss of any mechanism regulating V/Q distribution may be deleterious.