Studies of isolated pulmonary and systemic arteries show that the endothelium can influence vasoreactivity by releasing factors, in addition to prostaglandius, which either mediate of modulate the smooth muscle's response to certain dilator and constrictor stimuli. Although these in vitro observations and the incidence of endothelial and intimal lesions in various forms of pulmonary hypertension suggest the endothelium may play a direct role in pulmonary vasoregulation, little is known about the importance of mechanisms of endothelial control of the intact pulmonary circulation. Thus the overall objective of this project is to define the significance and mechanisms of active endothelial regulation of both the normotensive and the hypertensive pulmonary circulation. Parallel experiments (bioassay, isometric tension, perfusion pressure, hemodynamic, and histological measurements) will be performed with isolated, large and small, bovine and rat pulmonary arteries, isolated rat lungs, intact catheterized rats, and bovine and rat pulmonary endothelial cell cultures to test: if pulmonary artery endothelium generates spontaneously or in response to certain dilator and constrictor stimuli a nonprostaglandin vasodilator, i.e., an endothelim-derived relaxing factor (EDRF), which helps maintain the low vascular tone and reactivity of the normal pulmonary circulation; if an endothelium-derived substance plays either a direct or an indirect, mediatory or modulatory role in the mechanism of acute hypoxic pulmonary vasoconstriction; and whether the endothelium has an active, mediatory or modulatory role in conrtolling pulmonary vascular tone during development of various types of pulmonary hypertension, i.e., during development of pulmonary hypertension in rats caused by exposure to hypoxia, monocrotaline, or aplha-naphthylthiourea. In the various experiments and vascular preparations, the release or action of an EDRF, or other endothelium-derived substances will be inhibited by endothelial denudation and/or by chemical agents. The insights gained from these animal studies will be useful in developing more effective vasodilators for the prevention or treatment of the debilitating pulmonary hypertension associated with chronic obstructive pulmonary disease, adult respiratory distress syndrome, recurrent pulmonary microembolism, unexplained pulmonary hypertension, and certain cardiac diseases.
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