LIPID MODULATORS OF PULMONARY VASCULAR TONE

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Although formation of 20-HETE in pregnant rabbit lungs was described over 20 years ago, no physiologic role for products of the cytochrome P450 4A enzyme system in the pulmonary system has been established. We recently described a dose dependent, cyclooxygenase dependent vasodilator action of 20-HETE on isolated human pulmonary arteries. We also identified immunospecific proteins and synthesis of 20-HETE from arachidonic acid in whole lung microsomes of patients, demonstrating that 20-HETE is an endogenous product of human lungs. The goal of our experiments is to examine the cellular sources and mechanisms which underlie 20-HETE induced vasodilation using a rat lung model. Our preliminary data show that 20-HETE increases and cP450 4A inhibitors decrease the open probability of K+ channels in rat pulmonary artery vascular smooth muscle cells (PA VSM). We speculate that reduced availability of 20-HETE may contribute to acute hypoxia induced pulmonary vasoconstriction in that hypoxia inhibits 20-HETE synthesis and demonstrate that inhibition of cP450 4A with 17-ODYA augments the hypoxic pulmonary vasoconstrictive response in isolated perfused lungs. The specific aims of this grant are (1) to determine the cellular source(s) of 20-HETE formation and the identity of the cyclooxygenase metabolite of 20-HETE in lung tissue (2) to further examine the mechanisms behind the cyclooxygenase dependent 20-HETE induced vasodilation of isolated pulmonary arteries (3) to examine the contribution of cP450 4A to acute hypoxic vasoconstrictive responses of isolated perfused lungs and (4) to study the ionic mechanisms which underlie 20-HETE induced vasodilation in isolated PA VSM. These experiments should provide important information about the sources and cellular/ionic mechanisms which mediate 20-HETE induced changes in isolated pulmonary vessel diameter, and position us to look for physiologic or pathophysiologic conditions in which cP450 4A products may alter pulmonary vascular tone.