PPARγ Dependence of Cyclosporine-Isoprenaline Renovascular Interaction: Roles of Nitric Oxide Synthase and Heme Oxygenase

We previously showed that cyclosporine (CSA) impairs renal vasodilations caused by b-adrenoceptor activation. This study investigated whether the peroxisome proliferator-activated receptor gamma (PPAR gamma) and related nitric oxide synthase (NOS)/heme oxygenase (HO) signaling mediates the CSA-beta-adrenoceptor interaction. The vasodilatory response elicited by a bolus injection of isoprenaline (1 mu mole) in phenylephrine-preconstricted perfused kidneys of rats was reduced after prior infusion of zinc protoporphyrin IX (ZnPP, HO inhibitor) or GW9662 (PPAR gamma antagonist), suggesting the involvement of PPAR gamma and HO-derived CO in the isoprenaline response. In contrast, the inhibition of NOS activity by N-G-nitro-L-arginine methyl ester had no effect on isoprenaline responses. CSA (5 mu M) significantly attenuated isoprenaline vasodilations, an effect that was abolished in the presence of GW9662 and accentuated by ZnPP. Also, supplementation with the PPAR gamma agonist pioglitazone or with L-arginine or hemin, substrates for NOS and HO, respectively, eliminated the unfavorable effect of CSA on isoprenaline vasodilations. The protection conferred by pioglitazone against CSA-evoked attenuation of isoprenaline vasodilations was maintained in N-G-nitro-L-arginine methyl ester-treated kidneys and disappeared after treatment with ZnPP or GW9662. In conclusion, the activation of the HO/CO/PPAR gamma cascade is probably the cellular mechanism that underlies the beneficial effect of pioglitazone on the CSA-isoprenaline interaction. Further, the facilitation of the HO/CO or NOS/NO pathway seems to offset this harmful effect of CSA.