Retinal plasma extravasation in streptozotocin-diabetic rats mediated by kinin B(1) and B(2) receptors.
OBJECTIVE
We investigated whether or not kinin receptors play a role in diabetic blood-retinal barrier breakdown, which is a leading cause of vision loss.


METHODS
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.).


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 B(1) receptor antagonists. Diabetes-induced plasma extravasation was inhibited only by a combination of des-Arg(10)-Hoe140 and Hoe 140 (100 nmol kg(-1), i.v. 15 min earlier) or by R-715 (1 micromol kg(-1), i.v.) injected daily for 7 days.


CONCLUSIONS
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.
Abdouh
M
M
Guy-Bernier Research Centre, Maisonneuve-Rosemont Hospital, Montréal, Canada.
Talbot
S
S
Couture
R
R
Hasséssian
H M
HM
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D052160:Benzothiazoles; D001813:Blood-Retinal Barrier / Q000502:physiology*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003959:Diamines; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000473:pathology; D005070:Evans Blue; D008297:Male; D009930:Organic Chemicals; D018384:Oxidative Stress / Q000187:drug effects; D010949:Plasma / Q000378:metabolism; D011804:Quinolines; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D012160:Retina / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000975:Antioxidants; D052160:Benzothiazoles; D003959:Diamines; D009930:Organic Chemicals; D011804:Quinolines; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C024626:bradykinin, des-Arg(9)-; C098022:SYBR Green I; D005070:Evans Blue; C065679:icatibant; D001920:Bradykinin; D000111:Acetylcysteine