内皮素-3对非糖尿病和糖尿病大鼠视网膜血流动力学的调节作用

Endothelin-3 regulation of retinal hemodynamics in nondiabetic and diabetic rats.

作者信息

Mori F, King G L, Clermont A C, Bursell D K, Bursell S E

机构信息

Research Division and Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

出版信息

Invest Ophthalmol Vis Sci. 2000 Nov;41(12):3955-62.

PMID:11053299

Abstract

PURPOSE

To investigate the mechanisms of action of endothelin (ET)-3 on the regulation of retinal hemodynamics in diabetic and nondiabetic rats.

METHODS

Retinal blood flow changes were measured using video fluorescein angiography. Measurements were made before and after intravitreal injections of different ET-3 concentrations in nondiabetic rats and rats with streptozotocin (STZ)-induced diabetes. The effect of ET-3 on retinal blood flow was also investigated in nondiabetic rats after pretreatment with N:(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase (NOS) inhibitor; BQ-788, an ET receptor B (ETB) antagonist; and BQ-123, an ET receptor A (ETA) antagonist. Control animals were injected intravitreally with vehicle alone.

RESULTS

In nondiabetic rats, ET-3 induced a dose-dependent rapid increase in retinal blood flow 2 minutes after intravitreal injection (maximal at 10(-)(8) M, P < 0. 01) followed 15 and 30 minutes after ET-3 injection by dose-dependent decreases in retinal blood flow (maximal effect at 10(-)(6) M, P < 0.05). The ET-3-stimulated retinal blood flow increase was inhibited by 10(-)(4) M BQ-788 (P < 0.01) and 10(-)(3) M L-NMMA (P < 0.05). The ET-3-stimulated decrease in retinal blood flow at later times (15 minutes) was inhibited (P < 0.03) by 10(-4) M BQ-123. In diabetic rats, baseline retinal blood flows were decreased compared with nondiabetic rats (P < 0.01), showed dose-dependent increases 2 minutes after ET-3 injection (P < 0.03), and at later times remained significantly increased (P < 0.05) in contrast to flows in nondiabetic rats.

CONCLUSIONS

The ET-3-induced initial rapid retinal blood flow increase in nondiabetic rats is mediated by the ET-3/ETB and NOS action. The subsequent retinal blood flow decrease is mediated by ET-3/ETA action. Diabetic rats showed comparable ET-3-induced retinal blood flow increases indicating normal ET-3/ETB action. However, at later times, retinal blood flow remained increased, suggesting an abnormal ET-3/ETA action.

摘要

目的

研究内皮素（ET）-3对糖尿病和非糖尿病大鼠视网膜血流调节的作用机制。

方法

使用视频荧光血管造影术测量视网膜血流变化。在非糖尿病大鼠和链脲佐菌素（STZ）诱导的糖尿病大鼠玻璃体内注射不同浓度的ET-3前后进行测量。还在非糖尿病大鼠中用一氧化氮合酶（NOS）抑制剂N：（G）-单甲基-L-精氨酸（L-NMMA）、内皮素受体B（ETB）拮抗剂BQ-788和内皮素受体A（ETA）拮抗剂BQ-123预处理后研究ET-3对视网膜血流的影响。对照动物仅玻璃体内注射赋形剂。

结果

在非糖尿病大鼠中，玻璃体内注射ET-3后2分钟，ET-3诱导视网膜血流呈剂量依赖性快速增加（在10^(-8) M时最大，P < 0.01），在ET-3注射后15分钟和30分钟，视网膜血流呈剂量依赖性下降（在10^(-6) M时效果最大，P < 0.05）。ET-3刺激的视网膜血流增加被10^(-4) M BQ-788（P < 0.01）和10^(-3) M L-NMMA（P < 0.05）抑制。ET-3刺激的后期（第15分钟）视网膜血流下降被10^(-4) M BQ-123抑制（P < 0.03）。在糖尿病大鼠中，与非糖尿病大鼠相比，基线视网膜血流降低（P < 0.01），ET-3注射后2分钟显示剂量依赖性增加（P < 0.03），与非糖尿病大鼠的血流相比，后期仍显著增加（P < 0.05）。