Differential effects of amrinone and milrinone upon myocardial inflammatory signaling.
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.


RESULTS
Primary rat cardiomyocyte cultures were treated with endotoxin (LPS) or tumor necrosis factor-alpha (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 micro mol/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.
D000676:Amrinone / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008833:Microcirculation / Q000166:cytology / Q000378:metabolism; D020105:Milrinone / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D002316:Cardiotonic Agents; D016207:Cytokines; D007527:Isoenzymes; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020105:Milrinone; D000676:Amrinone