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(Circulation. 1999;100:178-184.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Simvastatin Preserves the Ischemic-Reperfused Myocardium in Normocholesterolemic Rat Hearts
From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa, and the Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport (D.J.L.).
Correspondence to Dr Allan M. Lefer, Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107-6799.
Background—Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as cardiomyocyte injury. These deleterious effects are due in large part to endothelial dysfunction leading to the upregulation of cell adhesion molecules and subsequent neutrophil-endothelium interaction. At clinically relevant doses, simvastatin, an HMG-CoA reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. We wanted to test the effects of simvastatin on neutrophil-mediated cardiac dysfunction in a controlled model of myocardial ischemia-reperfusion.
Methods and Results—This study examines the effects of simvastatin in a neutrophil-dependent isolated perfused rat heart model of ischemia (I) (20 minutes) and reperfusion (R) (45 minutes) injury. Administration of simvastatin 25 µg/rat improved coronary flow and preserved left ventricular developed pressure (LVDP) and dP/dtmax, indexes of cardiac contractile function. Final LVDP was 95±5 mm Hg in I/R hearts perfused with PMNs and simvastatin, compared with 49±4 mm Hg in PMN-perfused I/R hearts receiving only vehicle (P<0.001). In addition, simvastatin significantly reduced PMN accumulation in the ischemic myocardium (P<0.01). In PMN-perfused rat hearts after I/R, simvastatin also significantly attenuated P-selectin expression, CD18 upregulation in rat PMNs, and PMN adherence to rat vascular endothelium. Significant, although less potent, effects were obtained with pravastatin.
Conclusions—These results provide evidence that HMG-CoA reductase inhibitors are potent and effective cardioprotective agents that inhibit leukocyte–endothelial cell interactions and preserve cardiac contractile function and coronary perfusion after myocardial ischemia and reperfusion. Moreover, these effects are unrelated to the cholesterol-lowering action of this agent and appear to be mediated by enhanced endothelial release of NO.
Key Words: simvastatin • ischemia • reperfusion • myocardium • leukocytes
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