CYP4A/CYP2C modulation of the interaction of calcium channel blockers with cyclosporine on EDHF-mediated renal vasodilations in rats

Journal Article · Wed Nov 01 04:00:00 EDT 2017 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2017.09.007· OSTI ID:22722948

Hammoud, Safaa H. ^[1]; Omar, Amal G. ^[2]

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1. Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University (Lebanon)
2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University (Egypt)

The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7 days. Blood pressure (BP) was measured by tail-cuff (plethysmography). Kidneys were then isolated, perfused with physiological solution containing L-NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor, DIC), and preconstricted with phenylephrine. CSA (25 mg kg{sup −1} day{sup −1} for 7 days) increased BP and augmented carbachol renal vasodilations. The co-treatment with verapamil (2 mg kg{sup −1} day{sup −1}) or nifedipine (3 mg kg{sup −1} day{sup −1}) abolished CSA hypertension and conversely affected carbachol vasodilations (increases vs. decreases). Infusion of MSPPOH (epoxyeicosatrienoic acids, EETs, inhibitor) reduced carbachol vasodilations in kidneys of all rat groups, suggesting the importance of EETs in these responses. By contrast, 20-Hydroxyeicosatetraenoic Acid (20-HETE) inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared by CSA treatment, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. Renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs/20-HETE) were increased in CSA-treated rats. Whereas the CYP2C/EETs effects of CSA were abolished by verapamil and intensified by nifedipine, the CYP4A/20-HETE effects were reduced by either CCB. Overall, nifedipine and verapamil blunts CSA hypertension but variably affected concomitantly enhanced EDHF-dependent renal vasodilations and alterations in CYP2C/CYP4A signaling. - Highlights: • CSA enhances EDHF-mediated renal vasodilation. • CSA increases renal CYP4A/CYP2C expressions and 20-HETE/EETs levels. • Verapamil and nifedipine differently influences CSA/EDHF interaction.

• OSTI ID: 22722948
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 334; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOLOGICAL AVAILABILITY
BLOOD PRESSURE
CALCIUM
CYCLOSPORINE
ENDOTHELIUM
INHIBITION
INTERACTIONS
KIDNEYS
MAGNESIUM 25
MODULATION
NITRIC OXIDE
RATS
VASODILATION