Pioglitazone Ameliorates Cyclosporine‐Induced Attenuation Of Carbachol Renovascular Vasodilations: Role Of PPARγ/Nitric Oxide Synthase Signaling

Abstract

We previously reported that cyclosporine A (CSA) impairs reno‐vascular reactivity. This study investigated the role of peroxisome proliferator‐activated receptor‐gamma (PPARγ)/NOS signaling in the CSA‐induced attenuation of endothelium‐dependent vasodilations in phenylephrine‐preconstricted perfused kidneys of rats. Bolus injection of carbachol (4 μmol) reduced the renal perfusion pressure (RPP) with a peak depressor effect observed at 2 min. CSA (5 μM) infusion attenuated carbachol vasodilations. Similar inhibitory effects on carbachol vasodilations were evident after infusion of NG‐nitro‐L‐arginine methyl ester (L‐NAME, NOS inhibitor) or GW9662 (PPARγ antagonist). The CSA‐evoked attenuation of carbachol vasodilation was abolished in presence of L‐NAME in contrast to no effect for GW9662. Pioglitazone, PPARγ agonist, abolished the attenuation of these responses elicited by CSA; an effect that was not manifest in presence of GW9662. The specificity of the interaction with carbachol was verified by the lack of effect of CSA on vasodilations caused by papaverine. It is concluded that the interruption of PPARγ/NOS signaling mediates, at least partly, the inhibitory effect of CSA on renovascular responses to carbachol. Further, functional NOS is necessary for the amelioration by pioglitazone of the CSA‐carbachol interaction.