Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 154, Issue 1, Pages 136-143Publisher
WILEY
DOI: 10.1038/bjp.2008.48
Keywords
bradykinin; B-1 receptors; B-2 receptors; retina; plasma extravasation; diabetes
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Background and purpose: We investigated whether or not kinin receptors play a role in diabetic blood-retinal barrier breakdown, which is a leading cause of vision loss. Experimental approach: Blood-retinal barrier breakdown was quantified using Evans blue, and expression of kinin B-1 receptor mRNA was measured using quantitative reverse transcrition-PCR. Diabetic rats (streptozotocin (STZ), 65 mg kg(-1)) received a single intraocular injection of bradykinin (BK) or des-Arg(9)-BK, alone, or in combination with antagonists for B-1 (des-Arg(10)-Hoe140, R-715) and/or B-2 (Hoe140) receptors, given intraocularly or intravenously (i.v.). Key results: In control rats, BK (0.1-10 nmol) dose-dependently increased plasma extravasation, which was inhibited by Hoe140 (0.2 nmol), whereas des-Arg(9)-BK (0.1 and 1 nmol) was without effect. B-1 receptor mRNA was markedly increased in retinas of diabetic rats, and this was prevented by N-acetyl-L-cysteine (1 g kg(-1) day(-1) for 7 days). Plasma extravasation in retinas of STZ-diabetic rats was higher than in controls and enhanced by des-Arg(9)-BK. Response to des-Arg(9)-BK was inhibited by intraocular or i. v. injection of B1 receptor antagonists. Diabetes-induced plasma extravasation was inhibited only by a combination of des-Arg(10)-Hoe 140 and Hoe 140 (100 nmol kg(-1), i. v. 15 min earlier) or by R-715 (1 mu mol kg(-1), i. v.) injected daily for 7 days. Conclusions and implications: Kinin B-1 receptors are upregulated in retinas of STZ-diabetic rats through a mechanism involving oxidative stress. Both kinin B-1 and B-2 receptors contribute to increased plasma extravasation in diabetic retinopathy. Chronic inhibition of both kinin receptors, possibly with antioxidant adjuvants, may be a novel therapeutic strategy for diabetic retinopathy.
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