波生坦拮抗内皮素受体对实验性糖尿病周围神经功能的影响

Effects of endothelin receptor antagonism with bosentan on peripheral nerve function in experimental diabetes.

作者信息

Stevens E J, Tomlinson D R

机构信息

William Harvey Research Institute, Department of Pharmacology, Queen Mary and Westfield College, London.

出版信息

Br J Pharmacol. 1995 May;115(2):373-9. doi: 10.1111/j.1476-5381.1995.tb15888.x.

DOI:10.1111/j.1476-5381.1995.tb15888.x

PMID:7670740

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1908327/

Abstract

The effects of the non-selective endothelin (ET) receptor (ETA/ETB) antagonist, bosentan, on sciatic nerve dysfunction in experimental diabetes were investigated. 2. Rats with 5-6 weeks untreated streptozotocin-diabetes exhibited characteristic slowed motor nerve conduction velocity (mean +/- s.d., 36.6 +/- 3.4 m s-1) and nerve laser Doppler flux (197 +/- 64 arbitrary units) compared to age-matched control animals (42.7 +/- 2.4 m s-1 and 398 +/- 77 arbitrary units, respectively). Preventative treatment of diabetic rats with bosentan at 100 mg kg-1 day-1 p.o. attenuated both these deficits (39.7 +/- 3.0 m s-1 and 305 +/- 56 arbitrary units, respectively) without affecting mean arterial pressure. 3. In control and untreated diabetic rats, ET-1, 1 nmol kg-1 i.v., caused an initial hypotension (duration, 30 +/- 13 and 26 +/- 9 s, respectively; change in mean arterial pressure, -27 +/- 13 and -25 +/- 7 mmHg, respectively) followed by prolonged hypertension (change in mean arterial pressure, 52 +/- 18 and 31 +/- 5 mmHg, respectively). Effectiveness of the chronic bosentan treatment was demonstrated by inhibition of the hypotensive response to ET-1 in treated diabetic rats (duration, 5 +/- 2 s; change in mean arterial pressure, -4 +/- 2 mmHg) although the hypertension was unaltered (change in mean arterial pressure, 32 +/- 9 mmHg). 4. Acute i.v. administration of 10 mg kg-1 bosentan caused variable and transient rises in nerve laser Doppler flux in control (78 +/- 63 arbitrary units) and untreated diabetic rats (93 +/- 77 arbitrary units). Acute bosentan blocked the hypotensive response to subsequent ET-1 administration and attenuated the later hypertension (change in mean arterial pressure, 21 +/-9 mmHg in control, 29 +/- 10 mmHg in diabetic).5. Our results indicate that oral treatment of diabetic rats with an ET receptor antagonist can improves ciatic nerve perfusion and conduction, suggesting that the vasoconstrictor action of endogenous ET may contribute to peripheral nerve dysfunction in experimental diabetes.

摘要

研究了非选择性内皮素（ET）受体（ETA/ETB）拮抗剂波生坦对实验性糖尿病大鼠坐骨神经功能障碍的影响。2. 与年龄匹配的对照动物相比（分别为42.7±2.4 m/s和398±77任意单位），未经治疗的链脲佐菌素诱导糖尿病5 - 6周的大鼠表现出特征性的运动神经传导速度减慢（平均值±标准差，36.6±3.4 m/s）和神经激光多普勒血流（197±64任意单位）。以100 mg kg-1 每日口服波生坦预防性治疗糖尿病大鼠可减轻这两种缺陷（分别为39.7±3.0 m/s和305±56任意单位），且不影响平均动脉压。3. 在对照和未经治疗的糖尿病大鼠中，静脉注射1 nmol kg-1 ET-1会引起初始低血压（持续时间分别为30±13和26±9 s；平均动脉压变化分别为-27±13和-25±7 mmHg），随后是持续性高血压（平均动脉压变化分别为52±18和31±5 mmHg）。慢性波生坦治疗的有效性通过抑制治疗的糖尿病大鼠对ET-1的降压反应得以证明（持续时间，5±2 s；平均动脉压变化，-4±2 mmHg），尽管高血压未改变（平均动脉压变化，32±9 mmHg）。4. 急性静脉注射10 mg kg-1波生坦可使对照大鼠（78±63任意单位）和未经治疗的糖尿病大鼠（93±77任意单位）的神经激光多普勒血流出现可变的短暂升高。急性给予波生坦可阻断随后给予ET-1的降压反应，并减轻后期高血压（对照大鼠平均动脉压变化为21±9 mmHg，糖尿病大鼠为29±10 mmHg）。5. 我们的结果表明，用ET受体拮抗剂口服治疗糖尿病大鼠可改善坐骨神经灌注和传导，提示内源性ET的血管收缩作用可能导致实验性糖尿病中的周围神经功能障碍。