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(Circulation. 2003;108:2381.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Thromboxane A₂ Regulates Vascular Tone via Its Inhibitory Effect on the Expression of Inducible Nitric Oxide Synthase

Takehiro Yamada, MS; Takayuki Fujino, MD; Koh-ichi Yuhki, MS; Akiyoshi Hara, PhD; Hideji Karibe, PhD; Osamu Takahata, MD; Yuji Okada, MD; Chun-Yang Xiao, PhD; Koji Takayama, MD; Shuhko Kuriyama, MD; Takanobu Taniguchi, MD; Takahiro Shiokoshi, MD; Yoshinobu Ohsaki, MD; Kenjiro Kikuchi, MD; Shuh Narumiya, MD; Fumitaka Ushikubi, MD

From the Department of Pharmacology (T.Y., T.F., K.Y., A.H., H.K., O.T., Y. Okada, C.-Y.X., K.T., S.K., F.U.), the Department of Biochemistry (T.T.), and the First Department of Internal Medicine (T.S., Y. Ohsaki, K.K.), Asahikawa Medical College, Midorigaoka-Higashi, Asahikawa, and the Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto (S.N.), Japan.

Correspondence to Fumitaka Ushikubi, Department of Pharmacology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan. E-mail ushikubi{at}asahikawa-med.ac.jp

Received December 31, 2002; de novo received May 6, 2003; revision received July 9, 2003; accepted July 11, 2003.

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.

Key Words: thromboxane • prostaglandins • nitric oxide • nitric oxide synthase • vasculature

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