This study aims to decipher the potential effects of nebivolol in prevention and/or regression of renal artery dysfunction in diabetes associated with hypertension. Renal arteries were isolated from 80 male mice divided into four experimental groups: (i) group D: diabetics, at 2 months since streptozotocin injection; (ii) group Din: mice that at the initiation of streptozotocin diabetes were treated with 10 mg/kg b.w./day nebivolol for 2 months, to test for the potential prevention of vascular dysfunction; (iii) group Dfin: mice that after 2 months of diabetes were treated daily with 10 mg/kg b.w./day nebivolol for additional 2 months, in order to follow the possible regression of the dysfunction, and (iv) controls (C), age-matched healthy animals. The following measurements were performed: arterial blood pressure, plasma glucose concentration, and the vascular reactivity of the renal arteries in response to noradrenaline (10(-4) M), acetylcholine (10(-4) M) and sodium nitroprusside (10(-4) M). To assess the molecular mechanisms involved in the reactivity of the renal artery, the contribution of mitogen-activated protein kinase (MAP kinase) pathway and of L-type voltage gated Ca(2+) channels (in the contractile response to noradrenaline), of nitric oxide (NO) and Ca(2+) activated K(+) channels (in the endothelium-dependent vasodilator response), and of cGMP (in the endothelium-independent vasodilator response) was examined by exposing the arteries to corresponding inhibitors, and by using myograph and patch-clamp techniques, immunoblotting and NO assays. Results showed that, group D was characterized by hyperglycemia (blood glucose concentration: 136.66 +/- 4.96 mg/dl, a value approximately 65% increased compared to group C) and hypertension (systolic blood pressure: 145.66 +/- 5.96 mm Hg, a value approximately 34% increased compared to group C). Compared to group D, group Din was characterized by diminished blood glucose concentration ( approximately 1.6 fold), reduced systolic and diastolic blood pressure ( approximately 1.3 fold) and heart rate ( approximately 1.6 fold), as well as by increased contractile response of the renal artery to noradrenaline ( approximately 1.84 fold) and of the impeded vasodilator response to acetylcholine ( approximately 1.81 fold) and sodium nitroprusside ( approximately 1.42 fold). Together, these effects demonstrate that administration of 10 mg/kg b.w./day nebivolol at the moment of diabetes induction has preventive effects, ameliorating diabetes dysfunctions. Compared to group D, group Dfin was characterized by diminished glucose concentration ( approximately 1.3 fold), reduced systolic and diastolic blood pressure and heart rate (both approximately 1.2 fold), and by augmentation of contractile response of the renal artery to noradrenaline ( approximately 1.62 fold) and of vasodilator response to acetylcholine ( approximately 1.13 fold) and sodium nitroprusside ( approximately 1.19 fold). These effects assess that administration of 10 mg/kg b.w./day nebivolol after 2 months of diabetes contributes to regression of diabetes-associated dysfunctionalies. Nebivolol influenced the molecular mechanisms involved in renal artery reactivity in diabetic and hypertensive mice: it increased the NO production and endothelial NO synthase (eNOS) protein expression, decreased the expression of proportional, variant protein in L-type calcium channels and Ca(2+) activated K(+) channels, and diminished the MAP kinase activity. The reported data suggest that nebivolol may offer additional vascular protection for treating diabetes associated with hypertension.

译文

:本研究旨在阐明奈必洛尔在与高血压相关的糖尿病中预防和/或预防肾动脉功能障碍的潜在作用。从80只雄性小鼠中分离肾动脉,将其分为四个实验组:(i)D组:糖尿病患者,注射链脲佐菌素后2个月; (ii)Din组:在链脲佐菌素糖尿病开始时,用10mg / kg b.w./天的奈必洛尔治疗小鼠2个月,以测试其潜在的预防血管功能障碍的能力; (iii)Dfin组:在糖尿病2个月后,每天接受10 mg / kg bw /天的奈必洛尔治疗的小鼠再持续2个月,以追踪功能障碍的可能消退;和(iv)对照组(C),年龄匹配的健康动物。进行了以下测量:动​​脉血压,血浆葡萄糖浓度和响应去甲肾上腺素(10(-4)M),乙酰胆碱(10(-4)M)和硝普钠(10(4 -4)M)。若要评估参与肾动脉反应的分子机制,有丝分裂原激活的蛋白激酶(MAP激酶)途径和L型电压门控的Ca(2)通道(对去甲肾上腺素的收缩反应),硝酸的贡献通过将动脉暴露于相应的抑制剂并通过使用肌电描记器来检查氧化物(NO)和Ca(2)激活的K()通道(在内皮依赖性血管舒张反应中)和cGMP(在内皮依赖性血管舒张反应中)和膜片钳技术,免疫印迹和NO分析。结果表明,D组的特征是高血糖症(血糖浓度:136.66 /-4.96 mg / dl,与C组相比,升高约65%)和高血压(收缩压:145.66 /-5.96 mm Hg,与C组相比,约增加了34%。与D组相比,Din组的特征在于血糖浓度降低(约1.6倍),收缩压和舒张压降低(约1.3倍)和心率(约1.6倍),以及肾脏的收缩反应增强动脉至去甲肾上腺素(约1.84倍),以及对乙酰胆碱(约1.81倍)和硝普钠(约1.42倍)的血管舒张反应受阻。这些作用加在一起表明在糖尿病诱发时给予10 mg / kg体重/天的奈必洛尔具有预防作用,可减轻糖尿病的机能障碍。与D组相比,Dfin组的特征是葡萄糖浓度降低(约1.3倍),收缩压和舒张压和心率降低(约1.2倍),以及肾动脉对去甲肾上腺素的收缩反应增强(约1.62)倍)和舒张剂对乙酰胆碱(约1.13倍)和硝普钠(约1.19倍)的反应。这些效果评估了糖尿病2个月后给予10 mg / kg b.w./天的奈比洛尔有助于糖尿病相关功能障碍的消退。奈必洛尔影响糖尿病和高血压小鼠肾动脉反应的分子机制:它增加了NO的产生和内皮NO合酶(eNOS)蛋白的表达,降低了L型钙通道和Ca(2)中比例蛋白,变异蛋白的表达。激活K()通道,并降低MAP激酶活性。报道的数据表明奈必洛尔可能为治疗高血压相关的糖尿病提供额外的血管保护作用。

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