Augmentation of nitric oxide is crucial for the time-dependent effects of rosiglitazone on blood pressure and baroreflex function in rats

Objectives To determine the time-dependent effects of rosiglitazone (RSG) on blood pressure ( MAP) and baroreflexsensitivity (BRS) and the involvement of nitric oxide (NO) in these effects. Methods Male Sprague-Dawley rats were treated with RSG (8mg/kg per day, orally) or saline for 4, 8 and 12 weeks. BRS was determined by linear regression method with bolus injections of phenylephrine (PE-BRS) or sodium nitroprusside (NP-BRS). Insulin sensitivity (M value) was determined by euglycemic hyperinsulinemic clamp study. Vascular and cardiac responsiveness to isoproterenol, acetylcholine and NP were determined after ganglionic blockade. Effects of endogenous NO were examined by N omega-nitro-L-arginine-methyl ester (L-NAME) administration. Results RSG treatment time-dependently decreased circulating lipids, insulin, glucose levels and insulin resistance (HOMA-IR) but increased plasma NOx levels. M values were progressively decreased in control rats, but remained unchanged in RSG-treated rats. Chronic RSG treatment progressively lowered MAP but reciprocally increased heart rate (HR). In addition, chronic RSG treatment significantly attenuated HR changes to methylatropine but enhanced HR changes to propranolol. Twelve-week RSG treatment enhanced PE-BRS which was suppressed by methylatropine but not propranolol, and attenuated NP-BRS which was sustained after methylatropine or propranolol. Moreover, 12-week RSG treatment also diminished cardiac responsiveness to isoproterenol and augmented vascular responsiveness to acetylcholine, but not to NP. L-NAME eliminated the differences in MAP and HR between groups, and reversed both RSG-induced enhanced PE-BRS and attenuated NP-BRS. Plasma NOx levels were highly correlated with RSG-mediated changes in the baseline MAP, HR and BRS. Conclusion These data suggest that RSG-induced NO production is important for the time-dependent effects of RSG on MAP and BRS in rats.