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目的研究不同剂量NG-硝基-L-精氨酸甲基酯(L-NAME)作用于心力衰竭(心衰)大鼠应用β3受体激动剂BRL37344(BRL)后的血流动力学、环-磷酸鸟苷(cGMP)含量和β受体mRNA表达水平,进一步明确β3受体在心衰中的作用途径和L-NAME的作用特点。方法将大鼠随机分为对照组(Ⅰ组)、异丙肾上腺素(Iso)组(Ⅱ组)、Iso+BRL组(Ⅲ组)、Iso+BRL+L-NAME低剂量组(5mg/kg体重,Ⅳ组)、Iso+BRL+L-NAME中剂量组(50mg/kg体重,Ⅴ组)、Iso+BRL+L-NAME高剂量组(100mg/kg体重,Ⅵ组)。测定(1)血流动力学:左室舒张末压(LVEDP),左室收缩末压(LVESP),左室压力最大上升、下降速率(±dp/dt)。(2)心肌cGMP含量。(3)心肌组织β1、β2、β3受体mRNA水平。结果①Ⅱ组较Ⅰ组±dp/dt绝对值、LVESP明显降低,LVEDP明显升高(除-dp/dtP<0.05,余均为P<0.01);Ⅲ组较Ⅱ组-dp/dt绝对值、LVESP明显下降,LVEDP明显升高(P<0·05),+dp/dt变化呈下降趋势,但差异无统计学意义;随着L-NAME剂量的增加,±dp/dt绝对值升高,LVEDP降低,但大剂量L-NAME应用后,血流动力学又有恶化倾向。②Ⅰ、Ⅱ、Ⅲ组cGMP水平呈逐渐上升趋势(均为P<0.01),应用L-NAME后随着剂量的增加Ⅳ、Ⅴ、Ⅵ组cGMP呈下降趋势,大剂量应用L-NAME后cGMP回到正常对照组水平。③Ⅰ、Ⅱ、Ⅲ组比较,β1受体mRNA/β-actinmRNA为Ⅰ组最高、Ⅲ组最低,差异有统计学意义(均为P<0.01);β2受体mRNA/β-actinmRNA呈下降趋势,但三组间差异无统计学意义;而β3受体mRNA/β-actinmRNA的三组中Ⅲ组最高、Ⅰ组最低,差异有统计学意义(均为P<0.01);而Ⅳ、Ⅴ、Ⅵ组三种β受体mRNA水平与Ⅲ组相似,差异无统计学意义。结论β3受体经NOS途径发挥作用,L-NAME可部分阻断β3受体激动剂对衰竭心脏的负性肌力作用,改善心功能,但大剂量应用会加重心衰进程。
Objective To study the hemodynamics of different doses of NG-nitro-L-arginine methyl ester (L-NAME) in rats with heart failure (CHF) treated with BRL 37344 (BRL) - guanosine monophosphate (cGMP) content and β receptor mRNA expression level, to further clarify the β3 receptor pathway in the role of heart failure and L-NAME features. Methods The rats were randomly divided into control group (group Ⅰ), Iso group (group Ⅱ), Iso + BRL group (Ⅲ group), Iso + BRL + L-NAME low dose group (Group Ⅳ), Iso + BRL + L-NAME middle dose group (50mg / kg body weight, group V) and Iso + BRL + L-NAME high dose group (100mg / kg body weight and group Ⅵ). (1) Hemodynamics: Left ventricular end-diastolic pressure (LVEDP), left ventricular end systolic pressure (LVESP), maximum increase of left ventricular pressure, and rate of decrease (± dp / dt) (2) myocardial cGMP content. (3) myocardial tissue β1, β2, β3 receptor mRNA levels. Results ① The absolute value of ± dp / dt, LVESP and LVEDP in group Ⅱ were significantly higher than those in group Ⅰ (P <0.01 except -dp / dtP <0.05) LVESP was significantly decreased, LVEDP was significantly increased (P <0.05), + dp / dt showed a downward trend, but the difference was not statistically significant; ± dp / dt absolute value increased with the increase of L-NAME dose, LVEDP decreased, but the application of high-dose L-NAME, hemodynamics have a tendency to worsen. ② The levels of cGMP in groups Ⅰ, Ⅱ and Ⅲ increased gradually (all P <0.01). The levels of cGMP in groupsⅤ and V were decreased with the increase of L-NAME, To normal control group level. The mRNA expression of β1 / β-actin was the highest in group Ⅰ and the lowest in group Ⅲ (all P <0.01) But the difference between the three groups was not statistically significant; while the group of β3 receptor mRNA / β-actinmRNA in group Ⅲ was the highest, group Ⅰ was the lowest, the difference was statistically significant (both P <0.01); while Ⅳ, Ⅴ, Ⅵ Group three β receptor mRNA levels similar to the group Ⅲ, the difference was not statistically significant. Conclusion The β3 receptor plays a role in NOS pathway. L-NAME can partially block the negative inotropic effect of β3 agonist on the failing heart and improve the cardiac function. However, the high dose of L-NAME can aggravate the progression of heart failure.