During congestive heart failure, the pulmonary vasculature is chronically exposed to high pulmonary vascular pressures. The hypothesis of this proposal is that in response to chronic hemodynamic stresses applied to the lung during heart failure, the lung vasculature is functionally as well as structurally remodeled. Since the microcirculation is the predominant locus of fluid and solute exchange and the control of microvascular resistance and flow distribution, the question of how acute land chronic hypertension specifically alter microcirculatory function is critical. Alterations may be seen with respect to microvascular exchange of fluid and proteins, vascular reactivity, endothelial vasodilator capacity, and vascular wall mechanics in the lung. Experiments are designed to address four specific aims: 1) To evaluate microvascular permeability in chronic pulmonary venous hypertension, specifically the effects of pulmonary venous pressure, angiotensin II, and atrial natriuretic factor; 2) To test the hypothesis that vasoconstrictor reactivity, i.e. the pulmonary vascular response to angiotensin II, arginine vasopressin, and KCl will be altered in a different manner by acute and chronic pressure stress; 3) To evaluate the effects of acute and chronic pressures stress on the efficacy of endothelial derived relaxing factors such as nitric oxide and prostacyclin; and 4) To determine if the altered vasoreactivity seen in response to acute or chronic pressure stress is related to vascular smooth muscle mechanics, i.e. whether pulmonary vessels subjected to normal or chronically elevated vascular pressures have unique active/passive length tension relationships, or to modifications in protein kinase C. Since the question of how restructuring has altered pulmonary microvascular function cannot be necessarily inferred from studies of main pulmonary artery rings, in this proposal, we will specifically focus on microvascular function utilizing both isolated perfused lung lobes and isolated segments of pulmonary arterial and venular microvessels. Responses in control lobes or vessels will be compared to those from animals with chronic pulmonary venous hypertension. In this hypertension model, animals are chronically instrumented for ventricular pacing, and paced at 240 beats/minute for 14-28 days.
