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J Thorac Cardiovasc Surg 1995;109:448-456
© 1995 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Acadesine inhibits neutrophil CD11b up-regulation in vitro and during in vivo cardiopulmonary bypass

New Haven, Conn.

Supported by National Institutes of Health grant HL47193 (B.R.S.) and Gensia Pharmaceuticals. Christine Rinder is a recipient of an American Heart Association Clinician-Scientist Award, and Brian Smith is a Scholar of the Leukemia Society of America.

Received for publication Feb. 10, 1994. Accepted for publication July 12, 1994. Address for reprints: Christine S. Rinder, MD, Department of Anesthesiology, Yale University School of Medicine, P.O. Box 208035, New Haven, CT 06520-8035.

Abstract

Granulocyte adhesion to ischemic tissue, mediated in large part byß₂ integrin receptors, is important in the pathophysiology of reperfusion injury. Acadesine, a drug that modulates adenosine levels in ischemic tissue, has been shown to reduce reperfusion injury in animal models of ischemia. The purpose of this study was to measure changes in granulocyte CD11b/CD18 in an in vitro assay and in an in vivo trial of acadesine administered during cardiopulmonary bypass to determine whether this incubated with acadesine or control diluent, stimulated with N-formyl-methionyl-leucylphenylalanine, and granulocyte CD11b measured. Acadesine significantly (p < 0.01) inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation by a mean of 61%. In similar experiments, adenosine also inhibited N-formylmethionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation (p < 0.01). In vivo, 34 patients at our institution participating in a multicenter trial of acadesine during cardiopulmonary bypass were randomized to placebo, low-dose, or high-dose acadesine infusion perioperatively. Combining low-and high-dose treatment groups, There was significant (p = 0.05) inhibition of granulocyte CD11b up-regulation in patients receiving acadesine; granulocyte CD11b expression in the acadesine group peaked at 2.8 times baseline versus 4.3 for placebo. By contrast, monocyte CD11b up-regulation (peaking after cardiopulmonary bypass at 3 times baseline) was not affected by acadesine. Acadesine and adenosine inhibit up-regulation of granulocyte cardiopulmonary bypass. This inhibition may contribute to the ability of these agents to decrease in vivo reperfusion injury. (J THORACCARDIOVASCSURG1995; 109: 448-56).

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