PPARγ Dependence Of the Cyclosporine‐Isoprenaline Renovascular Interaction: Roles of Nitric Oxide Synthase And Heme Oxygenase

Abstract

Cyclosporine (CSA) impairs renal vasodilations caused by β-adrenoceptor activation. The hypothesis was tested that the CSA-isoprenaline renal interaction is modulated by PPARγ and related NOS/HO signaling. Renal vasodilations caused by bolus isoprenaline (1 μmol) in phenylephrine-preconstricted perfused kidneys of rats was reduced after prior infusion of zinc protoporphyrin IX (ZnPP, HO inhibitor) or GW9662 (PPARγ antagonist) but not L-NAME (NOS inhibitor), suggesting the involvement of PPARγ and HO-derived CO in the isoprenaline response. CSA (5 μM) significantly attenuated isoprenaline vasodilations and this effect was abolished in presence of GW9662 but not L-NAME or ZnPP. Also, treatment with the PPARγ agonist pioglitazone or with L-arginine or hemin, substrates for NOS and HO, respectively, eliminated CSA-evoked reduction in isoprenaline responses. The protection conferred by pioglitazone against CSA-isoprenaline interaction was maintained in L-NAME-treated kidneys and disappeared after treatment with ZnPP or GW9662. In conclusion, the activation of the PPARγ/HO/CO cascade is probably the cellular mechanism that underlies the beneficial effect of pioglitazone on the CSA-isoprenaline interaction. Moreover, facilitation of NOS/NO or HO/CO signaling offsets the harmful effect of CSA on isoprenaline vasodilation.