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Enhanced Lipoxygenase/LTD4 Activity Accounts For The Exaggerated Hypertensive And Nephrotoxic Effects Of Cyclosporine Plus Indomethacin In Rats
Author(s) -
Helmy Maged W.,
Helmy Mai M.,
ElMas Mahmoud M.
Publication year - 2017
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.31.1_supplement.lb541
Subject(s) - endocrinology , medicine , montelukast , nephrotoxicity , blood urea nitrogen , pharmacology , blood pressure , chemistry , kidney , asthma
Cyclosporine (CSA) and indomethacin are usually co‐prescribed for some arthritic conditions. This combined regimen is often associated with rises in systolic blood pressure (SBP) and exaggerated nephrotoxicity. Here, we examined whether the 5‐lipoxygenase (LOX) pathway and its products, LTD4 and/or LTB4, modulate the hemodynamic and renal interactions of this regimen in rats. The oral 10‐day treatment with CSA (20 mg/kg/day) or indomethacin (5 mg/kg/day) (i) elevated serum creatinine and blood urea nitrogen, (ii) caused renal tubular atrophy and interstitial fibrosis, (iii) increased renal LTD4, LTB4, TNF‐α, TGF‐β1, caspase 3, and (iv) reduced renal PGE2 and total antioxidant capacity (TAC). Non‐invasive blood pressure measurements by tail‐cuff plethysmography revealed significant increases in SBP and heart rate in rats treated with CSA but not indomethacin. These structural, hemodynamic, and biochemical derangements were mostly intensified in rats treated simultaneously with CSA plus indomethacin. We also report that the concurrent administration of montelukast (cysteinyl LT receptor blocker), but not ONO‐4057 (LTB4 receptor blocker), ameliorated the CSA/indomethacin‐evoked hypertension and renal structural and biochemical indices. Compared with ONO‐4057, montelukast exhibited a greater capacity in reversing the inflammatory, oxidative, apoptotic, and fibrotic abnormalities induced by CSA/indomethacin. Moreover, montelukast abolished the increases in renal LTD4 in contrast to no effect for ONO‐4057. Both montelukast and ONO‐4057 reversed the CSA‐evoked increases in renal LTB4 but had no effect on the concomitant decreases in PGE2. Together, the inflammatory and oxidative effects that follow renal LOX upregulation and rise in cysteinyl LTD4 level might account for the aggravated hypertension and nephrotoxicity caused by the CSA/indomethacin regimen. The data uphold the therapeutic potential of cysteinyl LT receptors antagonism.