Cariporide (HOE 642) attenuates leukocyte activation in ischemia and reperfusion

Cariporide (HOE 642) ameliorates myocardial ischemia/reperfusion (I/R) injury, by the well established reduction of cytosolic [Ca(2+)] in cardiac myocytes through inhibition of Na(+)/H(+) exchange. However, postischemic inflammation also contributes to I/R injury. We tested the hypothesis that cariporide also modulates the inflammatory response. The effect of cariporide on L-selectin expression by human leukocytes in vitro and leukocyte adhesion and emigration in the reperfused rat cremaster muscle in vivo were studied. The rat cremaster muscle was exteriorized for intravital videomicroscopy, induction of ischemia (90 min), and reperfusion (90 min). Eleven rats were pretreated with cariporide (9 mg/kg body weight IV) whereas 11 rats received saline. Leukocyte adhesion was quantified offline. Human venous blood was incubated with cariporide (3 micromol/L) or saline, stimulated with formyl- methionine-leucine-phenylalanine (10(-10)-10(-6) mol/L), and granulocyte L-selectin expression was analyzed by flow cytometry. Cariporide reduced leukocyte rolling and adhesion by approximately 35% and 45%, respectively, after 30 min of reperfusion. Leukocyte extravasation was decreased by approximately 85% after 90 min. Cariporide increased L-selectin shedding at each formyl-methionine-leucine-phenylalanine concentration, reducing the 50% effective dose from 9.95 to 4.68 nmol/L. Thus, cariporide may ameliorate I/R injury not only by the known reduction of cytosolic [Ca(2+)] in cardiomyocytes, but also by attenuating leukocyte-dependent inflammatory responses. Promotion of L-selectin shedding from activated leukocytes may present a mechanism underlying this newly detected effect.

This study provides evidence that inhibition of Na(+)/H(+) exchange by cariporide (HOE 642) attenuates the postischemic inflammatory response. Leukocyte adhesion and emigration, assessed by in vivo microscopy, were markedly reduced in rat cremaster muscle, possibly because of increased L-selectin shedding of activated leukocytes as demonstrated by flow cytometry.