Differential effects of amrinone and milrinone upon myocardial inflammatory signaling

Article

关键词: TUMOR-NECROSIS-FACTOR;    CARDIOPULMONARY BYPASS;    PHOSPHODIESTERASE INHIBITORS;    ENDOTOXIC-SHOCK;    HEART-FAILURE;    NITRIC-OXIDE;    CYCLOOXYGENASE-2;    EXPRESSION;    CELLS;    MICE;   

DOI  :  10.1161/01.cir.0000032904.33237.8e

来源: SCIE

【 摘 要 】

Background-Mounting evidence links systemic and local inflammatory cytokine production to myocardial dysfunction and injury occurring during ischemia-reperfusion, cardiopulmonary bypass, and heart failure. Phosphodiesterase inhibitors (PDEIs), used frequently in these states, can modulate inflammatory signaling. The mechanisms for these effects are unclear. We therefore examined the effects of 2 commonly used PDEIs, amrinone and milrinone, on cardiac cell inflammatory responses. Methods and Results-Primary rat cardiomyocyte cultures were treated with endotoxin (LPS) or tumor necrosis factor-a (TNF-alpha), alone or in the presence of clinically relevant concentrations of amrinone or milrinone. Regulation of nuclear factor-kappa B (NFkappaB), nitric oxide synthase and cyclooxygenase isoforms, and cytokine production were assessed by electrophoretic mobility shift assays, Western immunoblotting, and enzyme-linked immunoassays, respectively. Both LPS and TNF-alpha induced significant NFkappaB activation, cyclooxygenase-2 (COX-2) expression, and inducible NO synthase (iNOS) and cytokine production; with the exception of COX-2 expression, all were significantly reduced by amrinone, beginning at concentrations of 10 to 50 mumol/L. In contrast, milrinone increased nuclear NFkappaB translocation, iNOS and COX-2 expression, and cardiomyocyte production of interleukin-1beta. Cell-permeable cAMP increased inflammatory gene expression, whereas cell-permeable cGMP had no effect, indicating that the effects of amrinone were not due to phosphodiesterase inhibition. Similar results were seen in macrophages and coronary vascular endothelial cells. Conclusions-Both amrinone and milrinone have significant effects on cardiac inflammatory signaling. Overall, amrinone reduces activation of the key transcription factor NFkappaB and limits the production of pro-inflammatory cytokines, whereas milrinone does not.

【 授权许可】

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