Thromboxane A(2) regulates vascular tone via its inhibitory effect on the expression of inducible nitric oxide synthase

Article

关键词: SMOOTH-MUSCLE-CELLS;    MICE LACKING;    PROSTANOID RECEPTORS;    SEPTIC SHOCK;    CYCLOOXYGENASE;    INDUCTION;    MACROPHAGES;    PHYSIOLOGY;    SYNERGISM;    RESPONSES;   

DOI  :  10.1161/01.CIR.0000093194.21109.EC

来源: SCIE

【 摘 要 】

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) A(2) and the iNOS-NO system, however, remain unknown. We intended to clarify the role of TXA(2), 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 TXA(2) 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 TXA(2) 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.

【 授权许可】

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