title: Thromboxane A2 regulates vascular tone via its inhibitory effect on the expression of inducible nitric oxide synthase.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Pharmacology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yamada
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujino
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Yuhki
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hara
authors.forename: Hideji
authors.initials: H
authors.lastname: Karibe
authors.forename: Osamu
authors.initials: O
authors.lastname: Takahata
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okada
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Xiao
authors.forename: Koji
authors.initials: K
authors.lastname: Takayama
authors.forename: Shuhko
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Takanobu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shiokoshi
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ohsaki
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ushikubi
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D016207:Cytokines / Q000494:pharmacology; D019446:Endotoxemia / Q000503:physiopathology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010656:Phenylephrine / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D013928:Thromboxane A2 / Q000819:agonists / Q000494:pharmacology / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D007213:Indomethacin