The research proposed in this application will investigate a previously undescribed effect of enesthetic agents to potentiate the production of vasoactive arachidonic acid mediators by the lung. The main hypothesis to be tested is that anesthetic agents affect biological membranes to increase the availability of arachidonic acid. Since the mechanism of anesthesia and the proposed mechanism of potentiation of mediator production both involve actions on membranes the phenomena should be related. We find that halothane potentiates mediator production over the same dose range that causes general enesthesia and propose to measure dose response relationships for a number of inhalation anesthetic agents having a wide range of lipid solubility. We also plan to investigate the mechanism of potentiation as well as the mechanisms of action of the mediators and of anesthetic agents on pulmonary vascular smooth muscle contraction, and pulmonary function. The pulmonary function tests to be used will be: dynamic compliance, single breath diffusing capacity for CO (DLCO), measurements of lung fluid balance, pulmonary vascular pressure and the permeability of the alveolar capillary membrane to macromolecules. We will measure arachidonate mediator concentration by radioimmunoassay and 14C radiochromatography. We have evidence that cyclic AMP and cyclic GMP may be involved in the effects of anesthetic agents on the lung and propose experiments to study this relationship. Most of the experiments will be done using the isolated perfused rabbit lung; however we will determine if anesthetic agents potentiate arachidonate mediator production in human lung. We believe that this research is important for two reasons: first it provides new insights into the ways in which anesthetic agents affect fundemental biological phenomena such as mediator production and the mechanisms of smooth muscle contraction. Second the work has clinical relevance. Since a number of stimuli including trauma and sepsis cause arachidonate mediator production in the lung, it is important to know if anesthetic agents augment mediator producion in a way which can be damaging to the lung and if inhibition of arachidonate synthesis can protect against such damage.
