Regulation of the Expression of Inducible Nitric Oxide Synthase by Prostanoids

Circulatory failure in septic shock is due to vascular hyporesponsiveness, in which a massive amounts of nitric oxide (NO) derived from inducible NO synthase (iNOS) plays a major role. In response to various inflammatory stimuli, prostanoids are also derived from inducible isoform of cyclooxygenase-2 (COX-2). Several reports on the cross talk between NO and prostanoids have been published; vasodilator prostanoids such as prostacyclin (PGI(2)) and prostaglandin E-2 enhance iNOS expression in cultured cells. However, the details of the cross talk between prostanoids and the iNOS-NO system remains unknown. We examined inflammatory 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 thromboxane A(2) (TXA(2)) receptor (TP-/- mice). The cytokine-induced iNOS expression and NO production were significantly augmented in TP-/- VSMCs. Furthermore, U-46619, a TP agonist, inhibited the cytokine-induced iNOS expression and NO production. The cytokine-induced hyporesponsiveness of aortas to vasoconstrictor was significantly augmented in TP-/- aorta. Finally, U-46619 significantly suppressed lipopolysaccharide-induced NO production in vivo in wild-type mice, however, this effect was not observed in TP-/- mice. These results suggest that TXA(2) has a protective role against the development of the vascular hyporesponsiveness via its inhibitory action on iNOS-NO system under pathological conditions such as sepsis. Thus, it seems that the cross-talk between PG and NO works to maintain the vascular homeostasis in the systemic inflammatory reactions such as sepsis.