The major objective of this research proposal is to test the hypothesis that elevated pulmonary vascular tone and lung injury alter the histaminergic, cholinergic, and adrenergic-mediated pulmonary vascular responses such that both pulmonary capillary pressure and microvascular permeability are affected, thereby disrupting lung fluid balance. Specifically, this proposal will: 1) characterize different models of elevated vascular tone with respect to the segmental distribution of vascular resistance-compliance, and microvascular permeability. The models of elevating vascular tone to be tested include U46619 (thromboxane analog), endothelin-I (vasoconstrictor peptide), norepinephrine, and angiotensin 11. 2) compare the responses to the activation of the histaminergic, cholinergic, and adrenergic receptor systems at normal vascular tone, and elevated vascular tone using the models outlined above, and following lung injury using phorbol myristate acetate (PMA) infusion, oleic acid infusion and HCL airway instillation. 3) compare the effect of active increases in vascular tone to passive vessel distention when the receptor systems stated above are stimulated; and 4) evaluate blood flow patterns that occur when the histaminergic, cholinergic, and adrenergic receptor systems are activated in lungs with normal vascular tone, elevated vascular tone, and injury. The segmental distribution of pulmonary vascular resistance and compliance will be determined by use of separate arterial, venous, and double vascular occlusion techniques. Pulmonary microvascular permeability will be evaluated by measurement of the capillary filtration coefficient, isogravimetric capillary pressure, and the osmotic reflection coefficient. In addition to physiological measurements, characterization of the histaminergic, cholinergic, and adrenergic receptor systems will be evaluated pharmacologically by kinetic rate-constant measurements and biochemically by assaying for the presence of vasoactive mediators. The effect of passive vessel distention on these receptor-mediated effects will be assessed by perfusion with different hydrostatic pressures. Finally, pulmonary blood flow patterns upon receptor stimulation will be evaluated by observing the distribution of zinc cadmium sulfide compound (a yellow fluorescing vascular marker) in control, vascular toned, and injured lungs.
