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 micrograms/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 micrograms/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.