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Heme oxygenase byproducts variably influences myocardial and autonomic dysfunctions induced by the cyclosporine/diclofenac regimen in female rats
Author(s) -
Ibrahim Karim S,
ElYazbi Ahmed F,
ElGowelli Hanan 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.1070.13
Subject(s) - heme oxygenase , hemin , bilirubin , medicine , endocrinology , nitric oxide , chemistry , pharmacology , heme , biochemistry , enzyme
We recently reported that simultaneous exposure to cyclosporine (CSA) and diclofenac (DIC) causes hypertension and left ventricular (LV) and arterial baroreceptor dysfunction in conscious female rats. In this study we tested the hypothesis that these CSA effects could be mitigated by facilitated heme oxygenase (HO) signaling. Experiments were performed in female rats to assess the effects of 10‐day treatment with the CSA (25 mg/kg/day)/diclofenac (1 mg/kg/day) regimen on cardiovascular functions in the absence and presence of pharmacologic maneuvers that upregulate HO or its enzymatic products. The hypertensive effect of CSA/DIC and associated shift in cardiac sympathovagal balance towards parasympathetic dominance (i.e. reduced low‐frequency/high‐frequency spectral ratio) were blunted upon concurrent treatment with hemin (HO‐1 inducer), tricarbonyldichlororuthenium (II) dimer (CORM‐2, carbon monoxide‐releasing molecule), or bilirubin. Whereas none of the latter treatments affected the CSA/DIC‐evoked decreases in the isovolumic relaxation constant (Tau, τ, a measure of cardiac diastolic function), the increases in LV contractility (dP/dt max ) in CSA/DIC‐treated rats were abolished by bilirubin only. Further, measurement of arterial baroreflex activity by the vasoactive method showed that bilirubin reversed the attenuated reflex bradycardia in contrast to no effect for hemin or CORM‐2. Paradoxically, the attenuated reflex tachycardia caused by CSA/DIC treatment was improved in presence of hemin and CORM‐2, but not bilirubin. All the favorable effects of hemin disappeared in rats treated simultaneously with the NOS inhibitor L‐NAME. These finding highlights key and NOS‐dependent modulatory roles for HO and the products of its enzymatic activity in improving the worsened cardiovascular profile in CSA/DIC‐treated female rats. Support or Funding Information Supported by the ALEX‐REP Grant Fund, Alexandria University, Egypt (Grant HLTH‐13‐01).