Augmentation of nitric oxide is crucial for the time-dependent effects of rosiglitazone on blood pressure and baroreflex function in rats.
OBJECTIVE
To determine the time-dependent effects of rosiglitazone (RSG) on blood pressure (MAP) and baroreflex sensitivity (BRS) and the involvement of nitric oxide (NO) in these effects.


METHODS
Male Sprague-Dawley rats were treated with RSG (8 mg/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 Nomega-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.


CONCLUSIONS
These data suggest that RSG-induced NO production is important for the time-dependent effects of RSG on MAP and BRS in rats.
Hsieh
Po-Shiuan
PS
Department of Physiology and Biophysics, National Defense Medical Center, Taipei.
Hong
Ling-Zong
LZ
D000284:Administration, Oral; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001286:Atropine Derivatives / Q000494:pharmacology; D001341:Autonomic Nervous System / Q000187:drug effects / Q000502:physiology; D017704:Baroreflex / Q000187:drug effects* / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D016014:Linear Models; D008055:Lipids / Q000097:blood; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D012680:Sensitivity and Specificity; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors
D001286:Atropine Derivatives; D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009569:Nitric Oxide; C006649:methylatropine; D011433:Propranolol; D019331:NG-Nitroarginine Methyl Ester