Role of arachidonic acid-derived metabolites in the control of pulmonary arterial pressure and hypoxic pulmonary vasoconstriction in rats.

Abstract

The roles of arachidonic acid (AA) metabolites in hypoxia-induced pulmonary vasoconstriction (HPV), a critical physiological mechanism that prevents ventilation/perfusion mismatch, are still incompletely understood. Pulmonary arterial pressure was measured in ventilated/perfused rat lungs. Isometric tones of rat intralobar pulmonary arteries were also measured, using a myograph. Hypoxia (Po₂, 3%)-induced pulmonary arterial pressure increases (ΔPAP(hypox)) were stable with blood-mixed perfusate, but decayed spontaneously. ΔPAP(hypox) was inhibited by 29%, 16%, and 28% by the thromboxane A₂ (TXA₂) antagonist SQ-29548, the 5-lipoxygenase inhibitor, MK886, and the leukotriene D₄ antagonist, LY-171883, respectively. The prostacyclin synthase inhibitor tranylcypromine augmented ΔPAP(hypox) by 5%, whereas inhibition of cytochrome P450 did not affect ΔPAP(hypox). Consistently, the TXA₂ analogue U46619 increased ΔPAP(hypox) whereas prostacyclin abolished ΔPAP(hypox). However, leukotriene D₄ had no direct effect on ΔPAP(hypox). In the isolated pulmonary arteries, pretreatment with U46619 was essential to demonstrate hypoxia-induced contraction. The above results suggest that TXA₂ and cysteinyl leukotrienes, other than leukotriene D₄, are endogenous factors that facilitate HPV in rats. The indispensable role of TXA₂-induced pretone in the HPV of isolated pulmonary arteries indicates that the signal from thromboxane receptors might be a critical component of oxygen sensation mechanisms.