Abstract
The endothelium‐derived hyperpolarizing factor (EDHF) is a back‐up mechanism that compensates for reduced nitric oxide (NO)/prodtanoids bioavailability. Here we investigated whether (i) cyclosporine (CSA, immunosuppressant drug) 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 combination for 7 days. Systolic blood pressure (SBP) was measured by Tail‐cuff plethysmography. Kidneys were then isolated, perfused with physiological solution containing L‐NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor), and preconstricted with phenylephrine. Carbachol vasodilations were established before and after the inhibition of 20‐HETE or EETs. CSA (25 mg.kg−1.day−1 for 7 days) increased SBP and augmented carbachol renal vasodilations. The concurrent administration of verapmil (2 mg.kg−1.day−1) or nifedipine (3 mg.kg−1.day−1) abolished the hypertensive effect of CSA and produced divergent effects on carbachol vasodilations (increases versus decreases). The infusion of MSPPOH (EETs inhibitor) reduced carbachol vasodilations in perfused kidneys of all rat groups, suggesting the importance of EETs in these responses. Moreover, HETE‐20 inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared in CSA‐treated, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. The renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs and 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 verapamil only. Overall, CYP2C/EETs and CYP4a/20‐HETE pathways variably modulate the contracting effects of nifedipine and verpamil on CSA‐evoked facilitation of EDHF‐dependent renal vasodilations. These effects may not be related to changes in SBP.Support or Funding InformationSupported by the Lebanese National Council for Scientific Research (CNRS) Grant Award for Lebanese graduates (Awardee: Safaa Hammoud).
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