Early upregulation of kinin B1 receptors in retinal microvessels of the streptozotocin-diabetic rat
Early upregulation of kinin B1 receptors in retinal microvessels of the streptozotocin-diabetic rat
复制标题
DOI：
10.1038/sj.bjp.0705210
复制
发表时间：
2003-09-01
影响因子：
7.3
通讯作者：
Hasséssian, HM
中科院分区：
文献类型：
--
作者：
Abdouh, M;Khanjari, A;Hasséssian, HM
1观察链脲佐菌素糖尿病大鼠和年龄匹配的对照组大鼠视网膜微血管对激动素B-1和B-2受体激动剂和拮抗剂的反应。此外，还对对照组和STZ糖尿病大鼠视网膜进行了定量的体外放射自显影。在对照组中，B-2受体激动剂缓激肽(BK，0.1-50 nm)以浓度和时间依赖的方式扩张视网膜血管。这种作用可被B-2受体拮抗剂Hoe140(1um)完全阻断。B型受体激动剂Des-Arg(9)-BK(0.1-50 nM)无此作用。3 Des-Arg(9)-BK在注射STZ后4d即可产生浓度依赖性的血管扩张，1 nM的Des-Arg(9)-BK的作用可被B-1受体拮抗剂Des-Arg(10)-Hoe140(1um)所抑制。对照组大鼠视网膜可检测到低水平的B-1受体结合位点，但在STZ糖尿病大鼠4天至21天的视网膜中密度高出256%。4在对照组大鼠，I nm BK的血管扩张既不涉及钙内流，也不涉及一氧化氮(NO)，因为GdCl3和L-NAME没有作用。然而，血管扩张确实涉及细胞内钙动员和环氧合酶-2(COX-2)途径的产物，因为2.5-二叔丁基对苯二酚(BHQ)、cADP核糖和L-745337抑制了这一反应。血管扩张反应被反式-2-苯基环丙胺(TPC)阻断，表明前列环素介导了这一反应。5在STZ-糖尿病大鼠，Des-Arg(9)-BK的血管扩张反应既涉及钙内流，也涉及细胞内钙从IP3敏感和非IP3敏感的商店动员。事实上，这种作用被GdCl3、BHQ和cADP核糖阻断。此外，NO的产生和COX-2途径的产物包括前列环素被L-NAME、L-745377和TPC.6抑制，1 nM BK或1 nM DES-Arg(9)-BK的血管扩张被NF023阻断，表明G(O)/G(I)G蛋白转导这两种作用。7这是关于视网膜循环的第一份报告，为血管扩张物质B-2受体和B-1受体上调提供证据。这些结果表明，激动素受体可能是治疗视网膜病变的潜在靶点。
1 Retinal microvessel responses to kinin B-1 and B-2 receptor agonists and antagonists were investigated in streptozotocin (STZ)-diabetic rats and age-matched controls. In addition, quantitative in vitro autoradiography was performed on retinas from control and STZ-diabetic rats with radioligands specific for B-2 ([I-125]HPP-Hoe 140), and B-1 receptors ([I-125]HPP-[des-Arg(10)]-Hoe 140).2 In control rats, the B-2 receptor agonist bradykinin (BK, 0.1 - 50 nm) vasodilated retinal vessels in a concentration and time-dependent manner. This effect was completely blocked by the B-2 receptor antagonist Hoe140 (1 muM). In contrast, the B, receptor agonist des-Arg(9)-BK (0.1 -50 nM) was without effect.3 Des-Arg(9)-BK was able to produce a concentration-dependent vasodilatation as early as 4 days after STZ injection, and the effect of 1 nM des-Arg(9)-BK was inhibited by the B-1 receptor antagonist des-Arg(10)-Hoe140 (1 muM). Low-level B-1 receptor binding sites were detected in control rats, but densities were 256% higher in retinas from 4- to 21-day STZ-diabetic rats.4 In control rats, the vasodilatation in response to I nm BK involved neither calcium influx nor nitric oxide (NO) as GdCl3 and L-NAME were without effect. However, the vasodilatation did involve intracellular calcium mobilization as well as products of the cyclooxygenase-2 (COX-2) pathway as 2.5-di-t-butylhydroquinone (BHQ), cADP ribose and L-745 337 inhibited this response. The vasodilatation response was blocked by trans-2-phenyl cyclopropylamine (TPC) demonstrating that prostacyclins mediate this response.5 In STZ-diabetic rats, the vasodilatation in response to des-Arg(9)-BK involved both calcium influx and intracellular calcium mobilization from stores both IP3 sensitive and non-IP3 sensitive. Indeed, the effect was blocked by GdCl3, BHQ and cADP ribose. Furthermore, NO production and products of the COX-2 pathway including prostacyclin are involved as the response was inhibited by L-NAME, L-745 377 and TPC.6 Vasodilatation in response to either 1 nM BK or 1 nM des-Arg(9)-BK were blocked by NF023 demonstrating that a G(o)/G(i) G-protein transduces both these effects.7 This is the first report on the retinal circulation which provides evidence for vasodilator B-2 receptors and the upregulation of B-1 receptors very early following induction of diabetes with STZ rats. These results suggest that kinin receptors may be potential targets for therapeutics to treat retinopathies.