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

Abstract

Background. 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. Methods. Pulmonary arterial pressure was measured in ventilated/perfused rat lungs. Isometric tones of rat intralobar pulmonary arteries were also measured, using a myograph. Results. Hypoxia (Po-2, 3%)-induced pulmonary arterial pressure increases (Delta PAP(hypox)) were stable with blood-mixed perfusate, but decayed spontaneously. Delta PAP(hypox) was inhibited by 29%, 16%, and 28% by the thromboxane A(2) (TXA(2)) antagonist SQ-29548, the 5-lipoxygenase inhibitor, MK886, and the leukotriene D-4 antagonist, LY-171883, respectively. The prostacyclin synthase inhibitor tranylcypromine augmented Delta PAP(hypox) by 5%, whereas inhibition of cytochrome P450 did not affect Delta PAP(hypox). Consistently, the TXA(2) analogue U46619 increased Delta PAP(hypox) whereas prostacyclin abolished Delta PAP(hypox). However, leukotriene D-4 had no direct effect on Delta PAP(hypox). In the isolated pulmonary arteries, pretreatment with U46619 was essential to demonstrate hypoxia-induced contraction. Conclusions. The above results suggest that TXA(2) and cysteinyl leukotrienes, other than leukotriene D-4, are endogenous factors that facilitate HPV in rats. The indispensable role of TXA(2)-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.