Hypoxic pulmonary vasoconstriction is an important regulatory mechanism for the balance of ventilation and perfusion protecting against hypoxemia. Hypoxic pulmonary vasoconstriction appears to be important for the fetus and the neonate. In various conditions of chronic lung disease such as chronic obstructive pulmonary disorders (COPD) and cystic fibrosis, hypoxia-induced pulmonary hypertension contributes to the development of cor pulmonale and the morbidity and mortality of these patients. The mechanism of hypoxic hypertension is unknown and unique to the lung circulation. Understanding of this mechanism would not only solve a vexing problem of modern physiology but lead to therapeutic interventions, beneficial for some patients with chronic lung diseases and pulmonary hypertension. Two major avenues of research have been pursued in an attempt to clarify the mechanism of thehypoxic pressure response. One avenue has been constructed to find a chemical mediator, the other to establish a direct effect of hypoxia on the pulmonary vessels. It is our hypothesis that arachidonate products of the lypoxygenase pathway (leukotrienes) are involves in the hypoxic pressor response either as mediators or as important amplifiers. We plan to investigate this hypothesis 1) on the level of the intact animal, 2) the isolated lung, and 3) the cellular level. We shall use inhibitors and stimulators of leukotriene synthesis, and study their effect on the hypoxic pressor response in the isolated lung from normal animals where dietary manipulation had led to impaired leukotriene synthesis. We shall attempt to remove all lipoxygenase products via column chromatography from the perfusate of isolated lungs and see whether their presence is obligatory for hypoxic vasoconstriction. We plan to measure with HPLC leukotriene production by isolated lungs and in lung lavage fluid obtained from hypoxic dogs and acutely and chronically hypoxic rats. Finally we shall explore various lung cell types as to their capacity to produce lipoxygenase products upon hipoxic challange.
