[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.
Yamada
Takehiro
T
Department of Hospital Pharmacy & Pharmacology, Asahikawa Medical College, Asahikawa, Hokkaido, Japan. yamadat@huhp.hokudai.ac.jp
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000502:physiology; D003864:Depression, Chemical; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011453:Prostaglandins / Q000502:physiology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000502:physiology*; D012772:Shock, Septic / Q000209:etiology*
D016207:Cytokines; D011453:Prostaglandins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2