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(Circulation. 2002;106:I-284.)
© 2002 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Differential Effects of Amrinone and Milrinone Upon Myocardial Inflammatory Signaling

Nikhil K. Chanani, BS; Douglas B. Cowan, PhD; Koh Takeuchi, MD; Dimitrios N. Poutias, BS; Lina M. Garcia, MD; Pedro J. del Nido, MD; Francis X. McGowan, Jr, MD

From the Departments of Anesthesia (N.K.C., D.B.C., K.T., D.N.P., F.X.M.) and Cardiac Surgery (L.M.G., P.J.d.N.), and the Anesthesiology/Critical Care Medicine Laboratory, Children’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Francis X. McGowan, Jr, MD, Department of Anesthesiology, Cardiac Anesthesia Service, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115. E-mail Francis.McGowan{at}tch.harvard.edu

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- (TNF-), alone or in the presence of clinically relevant concentrations of amrinone or milrinone. Regulation of nuclear factor-kappa B (NFB), 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- induced significant NFB 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 µmol/L. In contrast, milrinone increased nuclear NFB translocation, iNOS and COX-2 expression, and cardiomyocyte production of interleukin-1ß. 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 NFB and limits the production of pro-inflammatory cytokines, whereas milrinone does not.

Key Words: inflammation • nitric oxide synthase • inotropic agents • cytokines • phosphodiesterase inhibitor • cyclooxygenase