Hsieh Po-Shiuan, Hong Ling-Zong
Department of Physiology and Biophysics, National Defense Medical Center, Taipei.
J Hypertens. 2008 Jan;26(1):83-92. doi: 10.1097/HJH.0b013e3282f11934.
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.
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.
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.
These data suggest that RSG-induced NO production is important for the time-dependent effects of RSG on MAP and BRS in rats.
确定罗格列酮（RSG）对血压（平均动脉压，MAP）和压力反射敏感性（BRS）的时间依赖性影响，以及一氧化氮（NO）在这些影响中的作用。
雄性Sprague-Dawley大鼠分别接受RSG（8mg/kg/天，口服）或生理盐水处理4、8和12周。通过静脉注射去氧肾上腺素（PE-BRS）或硝普钠（NP-BRS）采用线性回归法测定BRS。通过正常血糖高胰岛素钳夹试验测定胰岛素敏感性（M值）。在神经节阻断后测定血管和心脏对异丙肾上腺素、乙酰胆碱和硝普钠的反应性。通过给予N-ω-硝基-L-精氨酸甲酯（L-NAME）研究内源性NO的作用。
RSG治疗呈时间依赖性降低循环脂质、胰岛素、血糖水平及胰岛素抵抗（HOMA-IR），但增加血浆NOx水平。对照组大鼠M值逐渐降低，而RSG治疗组大鼠M值保持不变。慢性RSG治疗使MAP逐渐降低，但使心率（HR）相应增加。此外，慢性RSG治疗显著减弱HR对甲基阿托品的变化，但增强HR对普萘洛尔的变化。12周RSG治疗增强了PE-BRS，其被甲基阿托品抑制但不被普萘洛尔抑制，同时减弱了NP-BRS，其在甲基阿托品或普萘洛尔作用后仍持续存在。此外，12周RSG治疗还减弱了心脏对异丙肾上腺素的反应性，增强了血管对乙酰胆碱而非硝普钠的反应性。L-NAME消除了各组间MAP和HR的差异，并逆转了RSG诱导的PE-BRS增强和NP-BRS减弱。血浆NOx水平与RSG介导的基线MAP、HR和BRS变化高度相关。
这些数据表明，RSG诱导产生的NO对RSG在大鼠中对MAP和BRS的时间依赖性影响具有重要作用。
