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Fumihiko Mori, George L. King, Allen C. Clermont, Dahlia K. Bursell, Sven-Erik Bursell; Endothelin-3 Regulation of Retinal Hemodynamics in Nondiabetic and Diabetic Rats. Invest. Ophthalmol. Vis. Sci. 2000;41(12):3955-3962.
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purpose. 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
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
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