Thromboxane A2 regulates vascular tone via its inhibitory effect on the expression of inducible nitric oxide synthase.
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.
Yamada
Takehiro
T
Department of Pharmacology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan.
Fujino
Takayuki
T
Yuhki
Koh-ichi
K
Hara
Akiyoshi
A
Karibe
Hideji
H
Takahata
Osamu
O
Okada
Yuji
Y
Xiao
Chun-Yang
CY
Takayama
Koji
K
Kuriyama
Shuhko
S
Taniguchi
Takanobu
T
Shiokoshi
Takahiro
T
Ohsaki
Yoshinobu
Y
Kikuchi
Kenjiro
K
Narumiya
Shuh
S
Ushikubi
Fumitaka
F
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*
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