However, the recent observation that an AT antagonist, but not antihypertensive therapy, ameliorates vascular pathology in the retina of certain diabetic rats implicates actions of RAS that are Bimatoprost independent of high blood pressure. Indeed, ANG II directly stimulates the expression of VEGF and VEGFR in retinal cells. ACE inhibition reduces retinal VEGF expression and hyperpermeability in diabetic rats.ACE inhibition also prevents retinal neovascularization and decreases VEGF, VEGFR, and angiopoietin expression in murine ischemiadriven retinopathy, and in the vitreous of patients with diabetic retinopathy. In spite of the above experimental evidence, blockage of RAS has shown little or no effect on retinal blood vessel abnormalities in clinical trials.Improvement of diabetic retinopathy was reported after RAS blockage in patients with normotensive type diabetes, but no benecial effect was reported in patients with hypertensive type diabetes. The reasons for this are unclear and may involve interaction with other members of RAS and the KKS. For example, activation of ACE can counterbalance the effects of ACE and ANG II by causing ANG II degradation and the production of ANG, suggesting that the deleterious effect of ANG II may be exacerbated by local ACE deciency.On the other hand, ACE catalyzes not only ANG II formation, but also the degradation of the vasodilator and proangiogenic peptide, BK.Recent evidence shows that BK increases vasopermeability in the healthy retina, that B receptors are upregulated in the retina of diabetic rats in response to oxidative stress, and that the blockage of both B and B receptors prevents the breakdown of the bloodretinal barrier associated with experimental diabetes. Furthermore, treatment with ACE inhibitors blocks oxidative stress and the induction of B receptors in diabetic rats, suggesting that these actions prevent the deleterious effects of BK accumulated in response to ACE inhibitors.Moreover, evidence that IGFI reverses protection by a GH antagonist against ischemiainduced retinopathy, and induces most of the alterations seen in diabetic retinopathy substantiates the causative role of the GHIGFI axis in the development of the disease.Various studies have demonstrated an increase in circulating IGFI in association with the presence or progression of the disease.Clinical trials with the GH antagonist pegvisomant yielded negative results, and the use of somatostatin analogs to block anterior pituitary GH secretion and to promote local somatostatin antiangiogenic actions on endothelial cells generated varying outcomes. The reasons for these discrepancies are unclear and are likely inuenced by small patient cohorts confounded not only by systemic factors such as glucose control, aggressive insulin treatment, and differential renal function, but also by ocular factors that modify the systemic incorporation or the local synthesis of GH, IGFI, and IGFI binding proteins. PRL may protect against diabetes, as suggested by the facts that PRL and PL promote the function, proliferation, and Carteolol hydrochloride survival of cells, and circulating PRL levels are often decreased in poorly controlled diabetic patients. However, studies measuring circulating PRL in association with diabetic retinopathy have reported increased levels.These contradictory observations may be due in part to the intraocular generation of vasoinhibins.Systemic PRL increases and gets processed to vasoinhibins in ocular uids and in retrolental brovascular membranes of patients with retinopathy of prematurity, a neovascular eye disease caused by elevated oxygen used to improve the survival of premature neonates.