Published Online
on March 1, 2004

A more recent version of this article appeared on April 1, 2004

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Submitted on October 2, 2003
Revised on October 23, 2003

ET_A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA-Salt Rats

Glaucia E. Callera; Augusto C. Montezano; Rhian M. Touyz; Telma M.T. Zorn; Maria Helena C. Carvalho; Zuleica B. Fortes; Dorothy Nigro; Ernesto L. Schiffrin; and Rita C. Tostes^*

From the Departments of Pharmacology (G.E.C., A.C.M., M.H.C.C., Z.B.F., D.N., R.C.T.) and Histology and Embryology (T.M.T.Z.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; and Clinical Research Institute of Montreal (G.E.C., R.M.T., E.L.S.), University of Montreal, Montreal, Canada.

^* To whom correspondence should be addressed. E-mail: rtostes{at}usp.br.

Abstract--Leukocyte adhesion to endothelial cells plays a key role in inflammatory processes associated with end-organ injury. Endothelin-1 (ET-1), which stimulates inflammatory processes, contributes to cardiovascular damage in deoxycorticosterone (DOCA)-salt hypertension. We investigated whether ET_A receptor blockade modulates in vivo leukocyte-endothelial cell interactions and expression of cell adhesion molecules (CAM) involved in these processes. DOCA-salt and control uninephrectomized rats were treated with the ET_A antagonist BMS182874 (40 mg/kg per day) or vehicle. Analysis of CAMs expression by reverse transcription-polymerase chain reaction and immunohistochemistry showed increased cardiac platelet selectin (P-selectin), detected mainly in endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1 (ICAM-1), in DOCA-salt rats. Cardiac expression of endothelial selectin (E-selectin) was decreased, whereas immunoreactivity to ED-1 and myeloperoxidase (MPO) activity, markers of macrophage and leukocyte infiltration, respectively, were increased in DOCA-salt. Leukocyte-endothelial cell interaction, functionally assessed in venules of internal spermatic fascia by intravital microscopy, was significantly altered in DOCA-salt rats as evidenced by increased leukocyte adhesion and decreased rolling. BMS182874 treatment normalized leukocyte-endothelium interactions, decreased cardiac VCAM-1 expression in DOCA and control groups, and had no effects on ICAM-1 expression. BMS182874 also increased E-selectin and abolished P-selectin expression in DOCA-salt, but not in control rats. The ET_A antagonist reduced cardiac ED-1 content and MPO activity and prevented cardiac damage in DOCA-salt rats. These data indicate that ET-1 participates, via activation of ET_A receptors, in altered leukocyte-endothelial cell interactions in DOCA-salt rats, possibly by modulating expression of CAMs, and that the inflammatory status is associated with cardiac damage in mineralocorticoid hypertension.

Key words: endothelin • deoxycorticosterone • arterial • hypertension • leukocytes • cell adhesion molecules

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