Endogenous bradykinin contributes to increased plasminogen activator inhibitor 1 antigen following hemodialysis

Abstract

Oxidative stress and inflammation predict cardiovascular events in chronic hemodialysis patients. Hemodialysis activates the kallikrein-kinin system, increasing bradykinin. Bradykinin promotes inflammation but also stimulates endothelial release of tissue-plasminogen activator and inhibits platelet aggregation. Understanding the detrimental and beneficial effects of endogenous bradykinin during hemodialysis has implications for the treatment of cardiovascular disease in the hemodialysis population. To test the hypothesis that bradykinin contributes to the inflammatory and fibrinolytic responses to dialysis, we conducted a double-blind, randomized, placebo-controlled crossover study comparing the effect of the bradykinin B(2) receptor blocker HOE-140 with vehicle on markers of oxidative stress, inflammation, fibrinolysis, and coagulation in nine hemodialysis patients without coronary artery disease. Bradykinin receptor antagonism did not affect the mean arterial pressure or heart rate response to dialysis. Monocyte chemoattractant protein 1 (MCP-1) peaked postdialysis; HOE-140 blunted the increase in MCP-1 (5.9 +/- 5.9 versus 25.6 +/- 20.1 pg/ml, P = 0.01). HOE-140 also abolished the increase in plasminogen activator inhibitor 1 (PAI-1) antigen observed at the end of dialysis. In contrast, HOE-140 significantly accentuated the effect of dialysis on F(2)-isoprostanes and P-selectin. Taken together, these results suggest that endogenous bradykinin contributes to increases in MCP-1 and PAI-1 antigen after hemodialysis via its B(2) receptor. Factors that increase the production of bradykinin or decrease its degradation may enhance the inflammatory response to hemodialysis.

Figure 1.

Effect of study drug and hemodialysis on MCP-1. *P < 0.05 versus T = 0 in post hoc analysis.

Figure 2.

Effect of study drug and hemodialysis on PAI-1. *P < 0.05 versus T = 0. †P = 0.02 for vehicle versus HOE-140 in post hoc analysis.

Figure 3.

Effect of study drug and hemodialysis on P-selectin. *P < 0.05 versus T = 0 in post hoc analysis. #P = 0.05 for vehicle versus HOE-140 in post hoc analysis.

Figure 4.

Study design.