Endothelin-3 regulation of retinal hemodynamics in nondiabetic and diabetic rats.
OBJECTIVE
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.
Mori
F
F
Research Division and Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
King
G L
GL
Clermont
A C
AC
Bursell
D K
DK
Bursell
S E
SE
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019334:Endothelin-3 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005451:Fluorescein Angiography; D006439:Hemodynamics / Q000187:drug effects; D007267:Injections; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012171:Retinal Vessels / Q000503:physiopathology*; D014822:Vitreous Body; D019323:omega-N-Methylarginine / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019334:Endothelin-3; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D019323:omega-N-Methylarginine; C086539:BQ 788; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C072247:cyclo(Trp-Asp-Pro-Val-Leu)