ramipril and Diabetic-Retinopathy

We report a case of acute renal insufficiency in a 77 year-old patient who took flurbiprofen as antiplatelet therapy. This is an important observation because it illustrates the potential risk of acute renal insufficiency, when using flurbiprofen before invasive medical examination or surgery in patients receiving long-term treatment with angiotensin converting enzyme inhibitors or angiotensin II inhibitors. This risk is probably underestimated in usual clinical practice.

Topics: Acute Kidney Injury; Aged; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Flurbiprofen; Humans; Male; Platelet Aggregation Inhibitors; Ramipril

To evaluate the effects of angiotensin-converting enzyme inhibitors (ACE-I) in retarding progression of severe non-proliferative diabetic retinopathy (NPDR) in normotensive type 2 diabetic patients.. This was a retrospective case control study of 128 patients with normotensive type 2 diabetes with lower than +1 dipstick proteinuria and severe NPDR who were classified into either an ACE-I treated group (Enalapril maleate 10 mg, n=12 , Ramipril 5 mg, n=17) or an ACE-I untreated group (n=99). Medical records were reviewed for endpoints of (a) occurrence of proliferative diabetic retinopathy (PDR) or macular edema (ME) for which laser phototherapy was necessary or (b) development of proteinuria of higher than +1 level requiring medication of ACE-I.. From the total of 128 patients, there were 29 ACE-I treated patients and 99 ACE-I untreated patients. There were no differences in the average age, duration of diabetes, body mass indices, blood pressure and levels of hyperglycemia or HbA1C between the two groups. Blood pressure and HbA1C levels in both groups remained unchanged during the study. The mean follow-up period was 41.6 months. In the ACE-I group, 6 patients progressed to PDR, 5 to ME and 6 developed proteinuria of greater than +1 over the follow-up period. In the control group, 30 patients progressed to PDR, 6 to ME and 9 developed proteinuria of greater than +1 over the follow-up period.. Small doses of ACE-I did not yield any beneficial effects in retarding the progression of severe NPDR.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Progression; Dose-Response Relationship, Drug; Enalapril; Female; Fundus Oculi; Humans; Male; Middle Aged; Ramipril; Retrospective Studies; Severity of Illness Index; Treatment Failure

To study if the endogenous renin-angiotensin system affects diabetic retinal leukostasis, rats with streptozotocin-induced diabetes were treated with an ACE inhibitor (ramipril), an angiotensin II AT(1) receptor antagonist (losartan) and the Ca channel blocker, (nifedipine). In the diabetic rats, these drug treatments reduced systolic blood pressure by approximately 16 mmHg but did not change blood glucose. After 2 weeks, the rats were examined for retinal leukostasis in vivo with a scanning laser ophthalmoscope (SLO). Retinal leukostasis, which was defined as no movement of arrested leukocytes over 2 min, was markedly higher in diabetic rats than normal controls (P<0.01). Leukostasis was significantly decreased by ramipril and losartan (P<0.01 vs. untreated diabetic rats) but was still higher than normal. Retinal leukostasis after nifedipine treatment was not significantly different than in untreated diabetic rats. The same trend was observed when leukostasis was analyzed on retinal flat mounts with concanavalin A and CD45 immunofluorescence; ramipril and losartan treatment, however, decreased leukostasis to values no different than controls. Retinal leukostasis was lowered by nifedipine (P<0.05, untreated diabetes vs. nifedipine-treated) but was still higher than in normal, ramipril-, or losartan-treated rats. Assays of gene expression of retinal intercellular adhesion molecule (ICAM-1) by semi-quantitative RT-PCR indicated that ICAM-1 mRNA was increased in diabetic rats but was decreased markedly by treatment with losartan or ramipril, and modestly by nifedipine. In summary, suppressing the activity of the endogenous renin-angiotensin system markedly decreases, perhaps even normalizes, the retinal leukostasis that accompanies type I diabetes in rats. These effects seem to be partly independent of blood pressure and to be associated with a decrease in ICAM-1 gene expression. Angiotensin II may, thus, mediate retinal leukostasis in early diabetes.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Concanavalin A; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Intercellular Adhesion Molecule-1; Leukocyte Common Antigens; Leukostasis; Losartan; Male; Nifedipine; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Ramipril; Rats; Rats, Long-Evans; Retina; Retinal Diseases

An active renin-angiotensin system has been found in the retina of rats and humans. Angiotensin-converting enzyme 2 (ACE2) is a recently discovered enzymatic homologue of Angiotensin-converting enzyme (ACE) that may be an important new component of the renin-angiotensin system (RAS). This study assesses the involvement of ACE2 in the normal and diabetic rodent retina and its modulation by ACE inhibition.. Sprague-Dawley rats were randomised into three groups, control, diabetes, and diabetes plus ramipril, with diabetes induced with the cell toxin streptozocin and the study run for 24 weeks. ACE2 and ACE gene levels were measured using quantitative real-time polymerase chain reaction (QRT-PCR), ACE2 protein expression was confirmed by Western blotting, and ACE and ACE2 catalytic activity were measured using specific activity assays in the rat retina. Localisation of ACE2 mRNA and protein were determined by in situ hybridisation and immunohistochemistry, respectively.. ACE mRNA levels were decreased to approximately 50% in the diabetic retina, but ACE2 mRNA levels were not significantly changed. ACE but not ACE2 gene expression was influenced by ramipril treatment. Following immunostaining, both ACE2 and ACE protein were localised predominantly to the inner nuclear layer (INL) but also to photoreceptors. In the diabetic retina, ACE enzyme activity was decreased, whereas ACE2 enzyme activity was increased.. This study has identified ACE2 gene and catalytically active protein in the rodent retina. In diabetes, the major changes were a decrease in ACE but an increase in ACE2 enzymatic activity. The ACE inhibitor ramipril did not reduce ACE2 enzymatic activity.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Carboxypeptidases; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Gene Expression Regulation, Enzymologic; Immunohistochemistry; In Situ Hybridization; Male; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Retina; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Angiotensin converting enzyme (ACE) inhibition has been recently suggested to have retinoprotective actions in diabetic patients but the mechanism of this effect is not known. In vitro, angiotensin II stimulates expression of vascular endothelial growth factor (VEGF), a permeability-inducing and endothelial cell specific angiogenic factor which has been implicated in the pathogenesis of diabetic retinopathy in humans and in experimental animals. We sought to determine the effects of ACE inhibition on retinal VEGF expression and permeability in experimental diabetic retinopathy.. Streptozotocin-induced diabetic rats and control animals were assigned at random to receive ACE inhibitor treatment or vehicle. At 24 weeks the retinal VEGF protein gene expression was assessed by northern blot analysis and in situ hybridisation. Retinal permeability to albumin was measured using a double isotope technique.. Experimental diabetes was associated with cell specific two to fourfold increase in retinal VEGF protein gene expression (p < 0.01) and a 2-fold increase in retinal vascular permeability to albumin (p < 0.01). The localization of VEGF expression in the retina was not altered in animals with experimental diabetes. Angiotensin converting enzyme inhibitor treatment of diabetic rats reduced diabetes-associated changes in VEGF gene expression and vascular permeability.. These findings implicate the renin-angiotensin system in the VEGF overexpression and hyperpermeability which accompany diabetic retinopathy and provide a potential mechanism for the beneficial effects of ACE inhibition in diabetic retinal disease.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Northern; Capillary Permeability; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelial Growth Factors; Gene Expression; In Situ Hybridization; Lymphokines; Male; Perindopril; Ramipril; Rats; Rats, Sprague-Dawley; Retina; Retinal Vessels; RNA, Messenger; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors