Although angiotensin converting enzyme (ACE) is important for controlling systemic blood pressure and sodium balance, recent evidence also indicates that ACE is important in the local tissue remodeling that accompanies various forms of injury. However, in humans, the potential importance of ACE has largely been inferred from the effects of ACE inhibitors on morbidity and mortality in various clinical trials, and not on direct assessments of tissue ACE expression i significantly increased in remodeling conducting pulmonary arteries in tissue obtained at the time of lung transplantation from patients with primary pulmonary hypertension (PPH). Thus, it is reasonable to hypothesize that ACE may also be important to the vascular remodeling that accompanies pulmonary vascular diseases like PPH. Traditionally, such a hypothesis would be tested in humans with a randomized placebo-controlled trial of an ACE inhibitor. However, supporting animal experimental data is limited to rodent models of the disease, and given the known risks of using vasodilators in PPH patients, the end-point for dosing in humans is also uncertain. Therefore, to be able to evaluate whether it is possible to inhibit lung ACE per se without causing systemic side effects, we have developed a safe, non- invasive, repeatable method to evaluate pulmonary ACE function using the radioactive ligand F-18 fluorocaptopril, and positron emission tomographic (PET) imaging. The method has been successfully implemented in animals and humans. Together with a recently developed large animal model of pulmonary hypertension, we plan to provide the needed evidence to support a clinical trial of the efficacy of ACE inhibition in PPH by meeting the following specific aims: 1) determine whether ACE expression is altered by, and whether ACE inhibition affects the development of, experimentally-induced pulmonary hypertension in a large animal model suitable for PET imaging; 2) determine whether pulmonary ACE expression is altered from normal in humans with PPH; and 3) determine an effective, safe dosing regiment of oral ACE inhibitor that will block at least 75% of lung ACE in vivo in humans with pulmonary hypertension. Not only will these studies help justify clinical trial ACE inhibitors in PPH or similar syndromes, but they will also be directly relevant to the eventual application of PET to studying other pulmonary receptor systems using radioligands developed in other projects of this Program.
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