Published Online
on October 13, 2003

A more recent version of this article appeared on November 11, 2003

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Submitted on December 31, 2002
Revised on July 9, 2003
Accepted on July 11, 2003

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, and 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.

^* To whom correspondence should be addressed. E-mail: ushikubi{at}asahikawa-med.ac.jp.

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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