The overall objectives of the proposed studies will be to define the biomechanical functions of the pulmonary vascular bed by using its measured geometric and mechanical characteristics, including how these characteristics are influenced by passive and vasoactive phenomena, and, by using more comprehensive deterministic models to evaluate hypotheses used to explain how the structure-function interactions produce the integrated behavior of the pulmonary vascular bed. These objectives will be achieved by addressing Specific Aims 1-5, which will be to: 1) fill in specific gaps in our knowledge of pulmonary vascular mechanics by measuring the influence of lung volume on the longitudinal distribution of pulmonary vascular resistance and the arterial:capillary:venous distribution of blood volume, the influence of hematocrit on the longitudinal distribution of vascular resistance, and the distribution of intravascular pressure as a function of vessel diameter; 2) determine the relative contributions of the dispersion of transit times along individual pathways and between parallel pathways through the pulmonary circulation to the total heterogeneity in pulmonary transit times; 3) determine how inspired nitric oxide concentration, blood flow rate, ventilation:perfusion ratio, and perfusate composition affect the size of the pulmonary arteries and veins accessible to vasodilator concentrations of NO when NO is added to the inspired gas; 4) determine whether increased shear stress on the endothelium is an NO mediated vasodilator stimulus in pulmonary arteries; and 5) continue to construct a deterministic mathematical model of the pulmonary vascular bed using data obtained in the accomplishment of the other Specific Aims. The model will be used to evaluate the ability of extant hypotheses to explain how the pulmonary vasculature functions by determining whether their predictions are quantitatively consistent with experimental observations, and to help guide experimental and theoretical investigations when they are not. The experiments will be carried out using isolated lungs from dogs and ferrets. These preparations will allow for the necessary control over the relevant variables. The methods will include the application of various indicator dilution concepts for evaluating pulmonary vascular function from measurements made outside the lungs, and they will include direct observations using microfocal angiography and dynamic image analysis. Some of the methods to be employed are new and/or unique to studies like those proposed. The expectation is that these methods will provide the means to solve significant problems that are as yet unresolved because available methods have not been applicable to the specific problems or because previous methods have provided apparently inconsistent results. Accomplishment of Specific Aims 1-5 will provide fundamental information necessary for a rational approach to evaluation and treatment of pulmonary vascular disease. In addition, Specific Aim 3 will provide specific information regarding the efficacy of NO inhalation as a pulmonary vasodilator therapy.
Specific Aim 4 will evaluate the potential role of a physiological pulmonary vasodilator mechanism that may help to maintain normally low pulmonary vascular tone in the face of normally present vasoconstrictor stimuli. The malfunction of such a mechanism may contribute to pulmonary hypertension of otherwise unknown etiology.
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