Pulmonary vascular effects of prostaglandin D₂, but not its systemic vascular or airway effects, are mediated through thromboxane receptor activation

Prostaglandin D₂ (PGD₂) can cause pulmonary vasoconstriction or vasodilation depending on animal species and age. Because the constrictor effects of PGD₂ in some vascular beds may be mediated through thromboxane receptors, the purpose of this study was to determine whether the vascular or bronchial effects of PGD₂ are mediated through thromboxane/endoperoxide (TX/E) receptor activation. In chronically instrumented awake sheep, PGD₂ (5-25 μg/kg i.v.) produced a dose-dependent increase in pulmonary arterial pressure and in systemic arterial blood pressure. These changes were due to increases in resistance, because cardiac output remained unchanged. PGD₂ also decreased dynamic compliance at lower doses (0.1-5 μg/kg i.v.) than those required to produce pulmonary vasoconstriction, confirming that PGD₂ is a potent bronchoconstrictor. The airway and systemic vascular effects of PGD₂ were not altered by TX/E receptor antagonism. In contrast, PGD₂-induced pulmonary vasoconstriction was blocked by two TX/E receptor antagonists, SQ-29,548 and AH-23848, implying that this effect is mediated through activation of TX/E receptors. The pulmonary vasoconstrictor effects of PGD₂ could not be explained by thromboxane generation, because neither cyclooxygenase inhibition with ibuprofen nor thromboxane synthase inhibition with OKY-046 had any effect on PGD₂ actions. In contrast, a mild but consistent pulmonary vasodilation produced by PGD₂ could be uncovered if the pulmonary vascular bed was preconstricted by hypoxia with simultaneous TX/E receptor blockade. These results indicate that TX/E receptor antagonists, although still useful pharmacological probes to determine the role of TX/E receptor activation in pathophysiological processes, should not be used to infer a role of endogenous thromboxane A₂. It is possible that PGD₂ participates in pulmonary processes previously ascribed uniquely to thromboxane A₂.