Alpha-adrenergic stimulation independent of hemodynamic changes and acute pulmonary vascular hypertension have been postulated as mechanisms in the development of pulmonary edema after a variety of clinical syndromes such as subarachnoid hemorrhage, intracranial hypertension, cerebral seizures, catecholamine overload, and exposure to high altitudes. In contrast to the possible permeability-increasing effects of excessive alpha-adrenergic stimulation, beta adrenergic agonists such as isoproterenol or terbutaline attenuate the edema that various agents can produce in peripheral and pulmonary vascular beds. The objectives of the proposed grant are two-fold: 1) to determine the pathogenesis of the neurogenic mediated pulmonary edema and 2) to determine the mechanism for the proposed """"""""anti-edema"""""""" effect of beta-agonistic drugs. The specific protocols will utilize four different experimental models: 1) massive alpha-adrenergic stimulation and acute pulmonary vascular hypertension will be produced in anesthetized dogs by a cisterna magna injection of sodium citrate; 2) acute pulmonary vascular hypertension will be produced in anesthetized dogs by mechanical elevation of left atrial pressure; 3) varying degrees of arterial and/or venous hypertension will be induced in isolated left lower lung lobes of dogs (Protocols 2 and 3 will serve as controls for the effects of vascular hypertension per se); and 4) the proposed permeability-increasing and decreasing effects of alpha- and beta-adrenergic stimulation, respectively, will be studied in cultured pulmonary artery endothelial cell monolayers and awake sheep. Alterations in transvascular fluid and protein fluxes will be assessed by measurement of lymph flow, lymph and plasma protein concentrations, the protein reflection coefficient, and extravascular lung water in intact animals, by measurement of the capillary filtration coefficient in isolated dog left lower lobes, and by measurement of 125I-albumin clearance in cultured endothelial cell monolayers. Morphologic alterations of the pulmonary endothelium, interstitium, and epithelium elicited by neurogenic mediated pulmonary edema will be characterized and correlated with the pathophysiologic abnormalities. A key structure - function relationship to be made is to correlate the amplitude and duration of the vascular hypertensive response with the degree of pulmonary pathology.
