Bradykinin stimulates ceramide production by activating specific BK-B1receptor in rat small artery

Abstract

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 by N-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 10−8M 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-B1antagonist Lys-Des-Arg9-Leu8-BK or the BK-B2antagonist HOE-140) are implicated in the BK-induced generation of ceramide. The BK-B2antagonist did not alter the effect of BK on ceramide generation, whereas the BK-B1antagonist 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.