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.
Callera
Glaucia E
GE
Department of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo-SP, Brazil.
Montezano
Augusto C
AC
Touyz
Rhian M
RM
Zorn
Telma M T
TM
Carvalho
Maria Helena C
MH
Fortes
Zuleica B
ZB
Nigro
Dorothy
D
Schiffrin
Ernesto L
EL
Tostes
Rita C
RC
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