Effects of Pioglitazone on Nitric Oxide Bioavailability Measured Using a Catheter-Type Nitric Oxide Sensor in Angiotensin II−Infusion Rabbit

Recently, peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been reported to increase nitric oxide (NO) bioavailability in vitro but not in vivo because of the difficulty of measuring plasma NO. Here, we investigated the effects of PPARgamma on plasma NO concentrations using the newly developed NO sensor in angiotensin II (Ang II)-infused rabbits. Male New Zealand rabbits were randomized for infusion with Ang II, either alone or in combination with pioglitazone (a PPARgamma agonist). Plasma NO concentration was measured using the catheter-type NO sensor placed in the aorta. We then infused N(G)-methyl-L-arginine (L-NMMA) and acetylcholine (ACh) into the aortic arch to measure the basal and ACh-induced plasma NO concentration. Vascular nitrotyrosine levels were examined by enzyme-linked immunoassay (ELISA). Both an immunohistochemical study and Western blotting were performed to examine the PPARgamma and gp91phox expression. The cotreatment with pioglitazone significantly suppressed the negative effects of Ang II, that is, the decreases in basal and ACh-induced NO production and the increase in vascular nitrotyrosine levels. Both the immunohistochemical study and Western blotting demonstrated that pioglitazone treatment enhaced PPARgamma expression and greatly inhibited Ang II-induced up-regulation of gp91phox. In conclusion, the PPARgamma agonist pioglitazone significantly improved NO bioavailability in Ang II-infused rabbits, most likely by attenuating nitrosative stresses.