Increases in leukostasis/monocyte adhesion to the capillary endothelium (leukostasis) and decreases in retinal blood flow may be causally associated and are implicated in the pathogenesis of diabetic retinopathy. In this study, we demonstrate that increases in leukostasis are observed in insulin-resistant states without diabetes, whereas decreases in retinal blood flow require diabetes and hyperglycemia. Microimpaction studies using beads mimicking retinal capillary obstruction by leukocytes did not affect retinal blood flow. In diabetic rats, treatment with the antioxidant ␣-lipoic acid normalized the amount of leukostasis but not retinal blood flow. In contrast, treatment with D-␣-tocopherol and protein kinase-C -isoform inhibition (LY333531) prevented the increases in leukostasis and decreases in retinal blood flow in diabetic rats. Serum hydroxyperoxide, a marker of oxidative stress, was increased in diabetic rats, but normalized by treatment with antioxidants ␣-lipoic acid and D-␣-tocopherol and, surprisingly, PKC -isoform inhibition. These findings suggest that leukostasis is associated with endothelial dysfunction, insulin resistance, and oxidative stress but is not related to retinal blood flow and is not sufficient to cause diabetic-like retinopathy. Moreover, treatment with PKC  inhibition is effective to normalize diabetes or hyperglycemia-induced PKC -isoform activation and oxidative stress. Diabetes 52:829 -837, 2003
Basic fibroblast growth factor (bFGF) stimulates angiogenesis and induces neural cell regeneration. We investigated the effects of bFGF on diabetic neuropathy in streptozotocin-induced diabetic rats. Diabetic rats were treated with human recombinant bFGF as follows: 1) intravenous administration, 2) intramuscular injection into thigh and soleus muscles with cross-linked gelatin hydrogel (CGH), and 3) intramuscular injection with saline. Ten or 30 days later, the motor nerve conduction velocity (MNCV) of the sciatic-tibial and caudal nerves, sensitivity to mechanical stimuli, sciatic nerve blood flow (SNBF), and retinal blood flow (RBF) were measured. Delayed MNCV in the sciatic-tibial and caudal nerves, hypoalgesia, and reduced SNBF in diabetic rats were all ameliorated by intravenous administration of bFGF after 10, but not 30, days. Intramuscular injection of bFGF with CGH also improved sciatic-tibial MNCV, hypoalgesia, and SNBF after 10 and 30 days, but caudal MNCV was not improved. However, intramuscular injection of bFGF with saline had no significant effects. bFGF did not significantly alter RBF in either normal or diabetic rats. These observations suggest that bFGF could have therapeutic value for diabetic neuropathy and that CGH could play important roles as a carrier of bFGF.
Aims/hypothesis. The renin angiotensin system is emerging as a potential therapeutic target for diabetic retinopathy. This study examines the effects of angiotensin-converting-enzyme inhibition by captopril and angiotensin AT 1 receptor antagonism using candesartan-cilexetil on retinal blood flow and acetylcholinestimulated vasodilatation in normotensive diabetic rats. Methods. Non-diabetic or streptozotocin-induced diabetic rats were treated for 2 weeks with captopril (100 mg/kg/day) or candesartan cilexetil (2 mg/kg/day). Retinal haemodynamics were measured using video fluorescein angiography. Effects of exogenous acetylcholine on retinal haemodynamics were examined following intravitreal injection. Total retinal diacylglycerol was labelled using diacylglycerol kinase, separated by thin-layer chromatography, and quantified using autoradiography. Results. Diabetic rats had prolonged retinal mean circulation time and decreased retinal blood flow compared with non-diabetic rats. Treatment of diabetic rats with either captopril or candesartan blocked the development of these blood flow abnormalities. Intraviteral injection of acetylcholine (10 −5 mol/l) in non-diabetic rats increased retinal blood flow by 53.9±22.0% relative to baseline whereas this response to acetylcholine was blunted in diabetic rats (4.4±19.6%, p<0.001). Candesartan treatment of diabetic rats restored the acetylcholine-stimulated retinal blood flow response to 60.0±18.7% compared with a 56.2+20.1% response in candesartan-treated non-diabetic rats. Total retinal diacylglycerol levels were increased in diabetic rats (3.75±0.98 nmol/mg, p<0.05) compared with non-diabetic rats (2.13±0.25 nmol/mg) and candesartan-treatment of diabetic rats normalized diacylglycerol levels (2.10±0.25 nmol/mg, p<0.05). Conclusion/interpretation. This report provides evidence that angiotensin-converting enzyme inhibition and AT 1 receptor antagonism ameliorates retinal haemodynamic dysfunctions in normotensive diabetic rats. [Diabetologia (2004) 47:113-123]
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