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A. C. Clermont, J. Liu, P. Riva, T. Kita, S. Sinha, T. Chilcote, E. P. Feener; Effects of Plasma Kallikrein on Retinal Vascular Functions in Diabetes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5035.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy and macular edema are associated with increases in retinal vascular permeability (RVP) and alterations in retinal blood flow (RBF). Previously, we have shown that plasma kallikrein (PK) is present in vitreous samples obtained from patients with advanced diabetic retinopathy and systemic administration of a PK inhibitor reduced RVP in rats with hypertension. In this study, we examine the effects of PK on RVP and RBF in rats with diabetes.
Diabetes was induced in Sprague Dawley rats by IP injection with streptozotocin. We administered the PK inhibitor (ASP-440) or vehicle alone via subcutaneous Alzet osmotic pumps immediately after confirmation of hyperglycemia (primary intervention study) or 2 weeks after diabetes onset (secondary intervention study). RVP and RBF were measured after 4 weeks of diabetes duration. Effects of direct administration of PK in the vitreous on RVP was measured following intravitreal injection of activated plasma kallikrein PK(act) in nondiabetic (NDM) or 4 week duration diabetic (DM) rats. RBF was measured using video fluorescein angiography. RVP was measured using Evan’s blue dye permeation and vitreous fluorophotometry.
In the primary intervention study, RVP increased 2.7 fold (p<0.01) in DM vehicle rats compared to NDM. ASP-440 decreased DM RVP by 42% (p=0.013) and 83% (p<0.001) at doses of 0.2 and 0.6 mg/kg/d, respectively. In the secondary intervention study, RVP was increased by 2.3 fold (p=0.002) in DM vehicle rats compared to NDM controls. Administration of ASP-440 at 0.6 mg/kg/d decreased DM RVP by 56% (p=0.011) compared to DM vehicle. In DM rats, retinal mean circulation time (MCT) was prolonged (1.62±0.3 vs 0.97±0.2 s, p<0.001) and RBF was reduced (152±33 vs 255±16, p=0.001) compared to NDM rats. Secondary intervention with ASP-440 improved DM MCT (1.26±0.3s, p=0.015) and RBF (240±68, p=0.001) compared to DM vehicle alone. Intravitreal injection of PK increased acute RVP by 34% (n=6) and 67% (n=9) compared to vehicle-injected eyes (both P<0.05)in NDM and DM rats respectively. The response to PK in DM rats was 74% greater (p=0.037) than in NDM rats.
These results show that systemic administration of the PK inhibitor, ASP-440, ameliorates retinal vascular abnormalities associated with diabetes. The effects of PK on the retinal vasculature in diabetes may be due to a combination of increased levels of PK and a hypersensitivity of the diabetic retina to PK’s actions.
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