We compared monotherapies and combinations of therapies that regulate G-protein–coupled receptors (GPCRs) with respect to their abilities to inhibit early stages of diabetic retinopathy (DR) in streptozotocin-diabetic mice. Metoprolol (MTP; 0.04–1.0 mg/kg b.wt./day), bromocriptine (BRM; 0.01–0.1 mg/kg b.wt./day), doxazosin (DOX; 0.01–1.0 mg/kg b.wt./day), or tamsulosin (TAM; 0.05–0.25 mg/kg b.wt./day) were injected individually daily for 2 months in dose-response studies to assess their effects on the diabetes-induced increases in retinal superoxide and leukocyte-mediated cytotoxicity against vascular endothelial cells, both of which abnormalities have been implicated in the development of DR. Each of the individual drugs inhibited the diabetes-induced increase in retinal superoxide at the higher concentrations tested, but the inhibition was lost at lower doses. To determine whether combination therapies had superior effects over individual drugs, we intentionally selected for each drug a low dose that had little or no effect on the diabetes-induced retinal superoxide for use separately or in combinations in 8-month studies of retinal function, vascular permeability, and capillary degeneration in diabetes. At the low doses used, combinations of the drugs generally were more effective than individual drugs, but the low-dose MTP alone totally inhibited diabetes-induced reduction in a vision task, BRM or DOX alone totally inhibited the vascular permeability defect, and DOX alone totally inhibited diabetes-induced degeneration of retinal capillaries. Although low-dose MTP, BRM, DOX, or TAM individually had beneficial effects on some endpoints, combination of the therapies better inhibited the spectrum of DR lesions evaluated.

中文翻译：

---

调节肾上腺素、血清素和多巴胺受体抑制糖尿病视网膜病变：单一疗法与联合疗法

我们比较了调节 G 蛋白偶联受体 (GPCR) 的单一疗法和联合疗法抑制链脲佐菌素糖尿病小鼠早期糖尿病视网膜病变 (DR) 的能力。美托洛尔（MTP；0.04–1.0 mg/kg b.wt./天）、溴隐亭（BRM；0.01–0.1 mg/kg b.wt./天）、多沙唑嗪（DOX；0.01–1.0 mg/kg b.wt.）在剂量反应研究中，每天单独注射坦索罗辛（TAM；0.05–0.25 mg/kg体重/天），持续两个月，以评估它们对糖尿病引起的视网膜超氧化物和白细胞增加的影响。介导针对血管内皮细胞的细胞毒性，这两种异常都与 DR 的发展有关。每种药物在较高的测试浓度下都能抑制糖尿病引起的视网膜超氧化物的增加，但在较低的剂量下就会失去抑制作用。为了确定联合疗法是否比单独药物具有更好的效果，我们在为期 8 个月的视网膜功能、血管研究中特意为每种药物选择了对糖尿病引起的视网膜超氧化物影响很小或没有影响的低剂量，单独使用或联合使用。糖尿病的渗透性和毛细血管变性。在低剂量使用时，药物组合通常比单独药物更有效，但单独使用低剂量 MTP 可以完全抑制糖尿病引起的视力下降，单独使用 BRM 或 DOX 可以完全抑制血管通透性缺陷，单独使用 DOX 可以完全抑制血管通透性缺陷。完全抑制糖尿病引起的视网膜毛细血管变性。尽管低剂量 MTP、BRM、DOX 或 TAM 单独对某些终点具有有益作用，但这些疗法的组合可以更好地抑制所评估的 DR 病变范围。