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Endothelin ETA/ETB receptors modulate the hemodynamic interaction of cyclosporine with selective and nonselective nonsteroidal antiinflammatory drugs in rats
Author(s) -
ElMas Mahmoud M,
AbdelHalim Rabab M,
Helmy Maged W,
ElGowelli Hanan M
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.654.8
Subject(s) - endothelin receptor , celecoxib , receptor , endothelin 1 , endocrinology , endothelins , medicine , downregulation and upregulation , blockade , pharmacology , hemodynamics , chemistry , biochemistry , gene
We tested the hypotheses that NSAIDs with different COX‐1/COX‐2 selectivity variably influence the hemodynamic effects of chronic cyclosporine (CSA) and that these interactions are causally related to alterations in endothelin receptors. Tail‐cuff measurements showed that CSA (20 mg/kg/day for 10 days) increased systolic blood pressure (SBP) and heart rate in rats. CSA also caused perivascular fibrosis of the renal arterioles along with opposite changes in the immunohistochemical signal of arteriolar ETA (increases) and ETB (decreases) receptors. In contrast to no effect for the COX‐1/COX‐2 inhibitor indomethacin, celecoxib (a selective COX‐2 inhibitor) abolished the pressor and tachycardic effects of CSA and associated changes in perivascuarr fibrosis and ETA/ETB protein expressions. The blockade of endothelin ETA receptors with atrasentan abolished the pressor, but not tachycardic, response elicited by CSA or its combination with indomethacin. Alternatively, BQ788, ETB receptor blocker, caused celecoxib‐sensitive elevations in SBP and potentiated the pressor response evoked by CSA. Collectively, opposite changes in vascular endothelin receptors (ETA upregulation and ETB downregulation) contribute to the pressor effect of chronic CSA. Moreover, ETB receptors mediate the protection offered by celecoxib against the adverse hemodynamic effects of CSA.