Endothelin-1 causes P-selectin-dependent leukocyte rolling and adhesion within rat mesenteric microvessels

Endothelin-1 (ET-1) is a potent vasoconstrictor postulated to play a role i n hypertension, ischemia-reperfusion, and atherosclerosis. In addition to t hese contributions, it has been also proposed to induce leukocyte-endotheli al cell interactions. The aim of the present study was to assess the mechan isms of action of ET-1 on leukocyte recruitment in vivo. Intravital microsc opy of the rat mesenteric postcapillary venules was used. Ten minutes after 1 nM ET-1 superfusion, a significant increase in leukocyte rolling (77.5 /- 22.6 vs. 20.5 +/- 4.5 cells/min) and adhesion (15.5 +/- 2.9 vs. 3.0 +/- 0.8 cells/100 mu m) but not emigration was observed. These effects were fou nd not to be mediated by mast cell activation. No platelet-endothelial cell interactions were detected in this in vivo system and furthermore, flow cy tometry analysis revealed no increase of P-selectin expression in rat plate lets on ET-1 stimulation. Pretreatment of animals with an anti-rat P-select in monoclonal antibody (mAb) dramatically reduced leukocyte rolling and adh esion by 100 and 94% respectively when compared with control mAb-treated an imals. At this dose of ET-1, a very transient decrease in shear rate was de tected, arteriolar diameter was significantly reduced but venular diameter remained unchanged. A similar mechanical reduction in blood flow did not in duce leukocyte recruitment. Thus this study demonstrates that ET-1 can dire ctly cause significant leukocyte rolling and adhesion adding to its potenti al pathophysiological role in the development of disease states of the card iovascular system.