The Lipopolysaccharide-Induced Up-Regulation of Bradykinin B_2-Receptor in the Mouse Heart Is Mediated by Tumor Necrosis Factor-α and Angiotensin II(Pharmacology)

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Our present study aimed to characterize the effects of lipopolysaccharide (LPS) on the expression of the bradykinin B_2-receptor in the mouse heart, which may have a role in cardiac depression during sepsis. We found that LPS induced the up-regulation of B_2-receptor mRNA in the heart in vivo and in cultured cardiac myocytes in vitro. Like LPS, tumor necrosis factor-α (TNF-α) but not interleukin (IL)-1-β, IL-6 or endothelin-1 stimulated B_2-receptor expression in cultured myocytes. The effect of LPS on the expression of B_2-receptor mRNA was also mimicked in cardiac myocytes by Ang II via Ang II type 1 (AT_1-) receptor. Losartan, an AT_1-receptor antagonist, inhibited about 50% of the LPS-induced up-regulation of B_2-receptor mRNA in the heart in vivo and in cultured cardiac myocytes in vitro. Furthermore, the up-regulation of B_2-receptor mRNA by either LPS or Ang II in cultured myocytes was abolished by anti-TNF-α antibody. These results suggest that the up-regulation of cardiac B_2-receptor expression by LPS is mediated through TNF-α, which is produced in the myocardium by two different mechanisms in an AT_1-receptor-dependent and independent manners, implying the role of the cardiac kallikrein-kinin system in the development of cardiac dysfunction during sepsis.
公益社団法人日本薬学会の論文
2006-06-01