Antagonism of leukotriene receptors and administration of a 5-lipoxygenase inhibitor do not affect hypoxic vasoconstriction

Abstract

The role of leukotrienes in hypoxic vasoconstriction remains controversial. Our previous study using the lipoxygenase inhibitor BW 755C in dogs failed to show a substantive role for leukotrienes in hypoxic vasoconstriction. To clarify further the role of leukotrienes, we designed 3 protocols. In the first protocol, we examined the effects of LTD4 boluses on the pulmonary circulation in 6 anesthetized dogs. LTD4, 1 microgram/kg, (a large dose relative to other species) produced no detectable constriction of the pulmonary artery, while systemic vascular resistance increased 41 +/- 17% (SD), left atrial pressure rose 3.5 +/- 1.5 mmHg, and cardiac output fell 18 +/- 8%. Two leukotriene receptor antagonists, LY171883 and L-648051, decreased these effects by more than 50%. In the second protocol, we tested these antagonists in 7 anesthetized, paralyzed, closed-chest dogs with acute left lower lobe atelectasis. Two manifestations of hypoxic vasoconstriction were examined: shunt fraction (as an inverse indicator of regional constriction in response to local hypoxia) and the pulmonary pressor response to global alveolar hypoxia (as an index of general hypoxic vasoconstriction). During normoxia before administration of the inhibitor, shunt fraction, measured using an SF6 infusion, was 25 +/- 7%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient (PDG) produced by 10% O2 inhalation, averaged +10.5 +/- 3.6 mmHg. The increase in pulmonary vascular resistance (PVR) with hypoxia was +2.4 +/- 1.7 mmHg/L/min. Then, during normoxia, 1 of the 2 antagonists was administered. Shunt fraction was unchanged (26 +/- 4%; p = 0.5). The pressor response to hypoxia was slightly less but remained substantial (the increase in PDG with hypoxia was +7.9 +/- 2.8 mmHg; p less than 0.05; the increase in PVR was +1.8 +/- 1.2 mmHg/L/min, p less than 0.10). In the third protocol we gave RG 5901, a relatively specific 5-lipoxygenase inhibitor, to 5 dogs with lobar atelectasis. The indices of hypoxic vasoconstriction were not affected by RG 5901. Shunt fraction was 29.5 +/- 8.1% before and 27.0 +/- 7.4% after RG 5901 (p greater than 0.05). The pressor response to hypoxia was +8.9 +/- 2.1 mmHg before and +8.7 +/- 3.7 mmHg after RG 5901 (p greater than 0.05). We conclude that in dogs, hypoxic vasoconstriction does not appear to be mediated by leukotrienes.