Heart and Circulatory Physiology

Bradykinin stimulates ceramide production by activating specific BK-B1 receptor in rat small artery

Leonard Kleine, Gele Liu, Normand Leblanc, Richard L. Hébert


Bradykinin (BK), a proinflammatory factor and vasodilator, causes functional change of the small artery. However, it is not clear whether any of these changes induced by BK are mediated byN-acetyl-d-sphingosine (ceramide). Therefore, we investigated whether BK affects the hydrolysis of sphingomyelin and generation of ceramide in the intact rat small artery. Our results suggest that BK induces sphingomyelin hydrolysis and increases ceramide production in a time- and dose-dependent manner. Relative to controls, BK causes a 50% decrease in sphingomyelin levels. Ceramide levels increase in response to BK with the highest level being obtained with 10−8 M BK as well as similar amounts of ceramide are generated when exogenous sphingomyelinase (SMase) is added. We then determined which of the two BK receptors (BK-B1 antagonist Lys-Des-Arg9-Leu8-BK or the BK-B2antagonist HOE-140) are implicated in the BK-induced generation of ceramide. The BK-B2 antagonist did not alter the effect of BK on ceramide generation, whereas the BK-B1 antagonist blocked the BK-induced production of ceramide. Although ceramide had no effect on KCl-induced constrictions, ceramide dilated preconstricted (phenylephrine) small pressurized rat mesenteric arteries by ∼40%. These results suggest that the activation of the BK-B1receptor mediates the BK-induced activation of SMase and of the production of ceramide. In conclusion, BK-mediated effects on vascular tone may be due, at least in part, to the increased production of ceramide.

  • phenylephrine
  • receptor antagonists
  • sphingomyelin
  • vascular tone


  • * L. Kleine and G. Liu contributed equally to this work.

  • This study was supported by the Kidney Foundation of Canada, Canadian Institutes of Health Research Grant MT-14103 (to R. L. Hébert), by the Heart and Stroke Foundation of Québec, the Canadian Institutes of Health Research, and by the Montréal Heart Institute (to N. Leblanc). N. Leblanc holds a Fonds de la Recherche en Santé du Québec scholarship.

  • Address for reprint requests and other correspondence: R. L. Hébert, Dept. of Cellular and Molecular Medicine, Univ. of Ottawa, 451 Smyth Rd., Rm. 1337, Ottawa, Ontario K1H 8M5, Canada (E-mail: rlhebert{at}uottawa.ca).

  • The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • First published September 27, 2001; 10.1152/ajpheart.00379.2001

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