ETA receptor mediates altered leukocyte-endothelial cell interaction and adhesion molecules expression in DOCA-salt rats.
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 ETA 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 ETA 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 ETA 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 ETA 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.
Department of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo-SP, Brazil.
Glaucia E
GE
Callera
Augusto C
AC
Montezano
Rhian M
RM
Touyz
Telma M T
TM
Zorn
Maria Helena C
MH
Carvalho
Zuleica B
ZB
Fortes
Dorothy
D
Nigro
Ernesto L
EL
Schiffrin
Rita C
RC
Tostes
D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002634:Chemotaxis, Leukocyte; D003619:Dansyl Compounds / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000633:toxicity*; D004195:Disease Models, Animal; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D006978:Hypertension, Renovascular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007962:Leukocytes / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017673:Sodium Chloride, Dietary / Q000633:toxicity*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D015815:Cell Adhesion Molecules; D003619:Dansyl Compounds; D019040:E-Selectin; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D019007:P-Selectin; D044022:Receptor, Endothelin A; D017673:Sodium Chloride, Dietary; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; D003900:Desoxycorticosterone