Background— Circulatory failure in sepsis arises from vascular hyporesponsiveness, in which nitric oxide (NO) derived from inducible NO synthase (iNOS) plays a major role. Details of the cross talk between thromboxane (TX) A₂ and the iNOS–NO system, however, remain unknown. We intended to clarify the role of TXA₂, via the cross talk, in vascular hyporesponsiveness.

Methods and Results— We examined cytokine-induced iNOS expression and NO production in cultured vascular smooth muscle cells (VSMCs) and cytokine-induced hyporesponsiveness of the aorta from mice lacking the TXA₂ receptor (TP^−/− mice). The cytokine-induced iNOS expression and NO production observed in wild-type VSMCs were significantly augmented in TP^−/− VSMCs, indicating an inhibitory effect of endogenous TXA₂ on iNOS expression. Furthermore, in indomethacin-treated wild-type VSMCs, U-46619, a TP agonist, inhibited cytokine-induced iNOS expression and NO production in a concentration-dependent manner, effects absent from TP^−/− VSMCs. In an ex vivo system, the cytokine-induced hyporesponsiveness of aortas to phenylephrine was significantly augmented in TP^−/− aorta but was almost completely canceled by aminoguanidine, an iNOS inhibitor. Accordingly, cytokine-induced NO production was significantly higher in TP^−/− aorta than in wild-type aorta. Moreover, U-46619 significantly suppressed lipopolysaccharide-induced NO production in vivo only in wild-type mice.

Conclusions— These results suggest that TXA₂ has a protective role against the development of vascular hyporesponsiveness via its inhibitory action on the iNOS–NO system under pathological conditions such as sepsis.