Rodríguez-Gómez Isabel, Manuel Moreno Juan, Jimenez Rosario, Quesada Andrés, Montoro-Molina Sebastian, Vargas-Tendero Pablo, Wangensteen Rosemary, Vargas Félix
Departamento de Fisiología, Facultad de Medicina, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada. Universidad de Granada, Granada, Spain;
Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada. Universidad de Granada, Granada, Spain; Departamento de Fisiología, Facultad de Medicina, Murcia, Spain;
Am J Hypertens. 2015 Dec;28(12):1464-72. doi: 10.1093/ajh/hpv049. Epub 2015 Apr 23.
This study analyzed the effects of chronic administration of N[omega]-hydroxy-nor-l-arginine (nor-NOHA), an inhibitor of arginase, on the hemodynamic, oxidative stress, morphologic, metabolic, and renal manifestations of hyperthyroidism in rats.
Four groups of male Wistar rats were used: control, nor-NOHA-treated (10 mg/kg/day), thyroxine (T4)-treated (75 μg/rat/day), and thyroxine- plus nor-NOHA-treated rats. All treatments were maintained for 4 weeks. Body weight, tail systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, morphologic, metabolic, plasma, and renal variables were measured. Arginase I and II protein abundance and arginase activity were measured in aorta, heart, and kidney.
The T4 group showed increased arginase I and II protein abundance, arginase activity, SBP, HR, plasma nitrates/nitrites (NOx), brainstem and urinary isoprostanes, proteinuria and cardiac and renal hypertrophy in comparison to control rats. In hyperthyroid rats, chronic nor-NOHA prevented the increase in SBP and HR and decreased proteinuria in association with an increase in plasma NOx and a decrease in brainstem and urinary isoprostanes. In normal rats, nor-NOHA treatment did not significantly change any hemodynamic, morphologic, or renal variables. Acute nor-NOHA administration did not affect renal or systemic hemodynamic variables in normal or T4-treated rats.
Hyperthyroidism in rats is associated with the increased expression and activity of arginase in aorta, heart, and kidney. Chronic arginase inhibition with nor-NOHA suppresses the characteristic hemodynamic manifestations of hyperthyroidism in association with a reduced oxidative stress. These results indicate an important role for arginase pathway alterations in the cardiovascular and renal abnormalities of hyperthyroidism.
本研究分析了长期给予精氨酸酶抑制剂N[ω]-羟基-nor-L-精氨酸（nor-NOHA）对大鼠甲状腺功能亢进的血流动力学、氧化应激、形态学、代谢及肾脏表现的影响。
使用四组雄性Wistar大鼠：对照组、nor-NOHA处理组（10 mg/kg/天）、甲状腺素（T4）处理组（75 μg/大鼠/天）以及甲状腺素加nor-NOHA处理组。所有处理均持续4周。每周记录体重、尾动脉收缩压（SBP）和心率（HR）。最后，测量形态学、代谢、血浆和肾脏变量。测定主动脉、心脏和肾脏中精氨酸酶I和II的蛋白丰度及精氨酸酶活性。
与对照大鼠相比，T4组精氨酸酶I和II的蛋白丰度、精氨酸酶活性、SBP、HR、血浆硝酸盐/亚硝酸盐（NOx）、脑干和尿中异前列腺素、蛋白尿以及心脏和肾脏肥大均增加。在甲状腺功能亢进大鼠中，长期给予nor-NOHA可预防SBP和HR升高，并降低蛋白尿，同时血浆NOx增加，脑干和尿中异前列腺素减少。在正常大鼠中，nor-NOHA处理未显著改变任何血流动力学、形态学或肾脏变量。急性给予nor-NOHA对正常或T4处理大鼠的肾脏或全身血流动力学变量无影响。
大鼠甲状腺功能亢进与主动脉、心脏和肾脏中精氨酸酶的表达和活性增加有关。用nor-NOHA长期抑制精氨酸酶可抑制甲状腺功能亢进的特征性血流动力学表现，并降低氧化应激。这些结果表明精氨酸酶途径改变在甲状腺功能亢进的心血管和肾脏异常中起重要作用。
