Objective To investigate the distribution of captopril tablet in the ocular tissue of rabbit eye after intragastrical administration. Methods Captopril tablet was administrated to rabbits intragastrically, 5 mg for every time, twice a day, for 6 days running.Rabbits were sacrificed 1 h after the last administration, and the tissues including cornea, iris, aqueous humor, lens, vitreous and retina were collected. Captopril in the tissues were determined by HPLC-UV. Results The content of captopril in retina, iris, aqueous humor, vitreous, lens, cornea were(111.0±15.6), (61.1±28.6), (35.7±18.5), (16.6±2.4), (8.6±4.0), (4.1±1.4) μg·g-1, respectively. Conclusion After continuous administration of captopril ,there were difference in the distribution of captopril in various tissues of the eye, with the highest concentration in the retina, the second in the iris, the lowest in the lens and cornea.
IGICR,ROBINSON CJ,MILOSEVICZ,et al.Activity of renin and angiotensin I converting enzyme in retina and ciliary body(author's transl)[J].Lijec Vjesn,1977,99(8):482-484.
Igi04 R, Robinson CJ, Milosevi04 Z, Wilson CM, Erd02s EG.
LIH,WANG YS.An angiotensin-converting enzyme inhi-bitor modulates stromal-derived factor-1 through CD26/dipeptidyl peptidase IV to inhibit laser-induced choroidal neovascularization[J].Mol Vis,2013,19(22):1107-1121.
Abstract Stromal-derived factor (SDF)-1 is a chemokine that recruits bone marrow-derived endothelial precursor cells (EPCs) for choroidal neovascularization (CNV) development. Angiotensin-converting enzyme (ACE) inhibitors mediate the compensatory effects of ACE and CD26/dipeptidyl peptidase IV (DPP IV), which results in the degradation and inactivation of SDF-1 in vivo. ACE inhibitors, such as imidapril, exhibit potential antiangiogenic effects on laser-induced CNV in mice. The role that this imidapril-mediated effect plays in modulating SDF-1 signals has not been defined. The present study assessed the effect of the CD26/SDF-1 signaling pathway on the inhibitory effect of imidapril in CNV development. CNV was induced in C57BL/6J mice by focally rupturing Bruch's membrane using a 532-nm diode laser. The animals were pretreated with PBS, imidapril, diprotin-A (a DPP IV antagonist), or imidapril plus diprotin-A for 5 days before photocoagulation. Treatments were continued daily for 14 days following the laser induction. The normal control group did not undergo laser rupture or receive treatment. CD26 activity was measured using a substrate conversion assay and flow cytometry. SDF-1 levels in both the blood and the bone marrow were measured using an enzyme-linked immunosorbent assay, and the number of circulating endothelial progenitor cells (EPCs) and leukocytes was quantified. Functional analyses of circulating SDF-1 were performed using actin polymerization blood biomarker assays, and the CNV-related responses were evaluated using fluorescein angiography and isolectin-B4-labeled flatmounts. Imidapril directly amplified CD26 activity and had a minor effect on the number of CD26(+) cells in the bone marrow. However, decreased CD26 activity in the plasma was secondary to a decrease in the number of circulating CD26(+) cells and blood leukocytes. Furthermore, imidapril increased SDF-1 concentrations in the peripheral circulation via CD26-induced degradation of SDF-1 in the bone marrow, an effect that coincided with elevated numbers of circulating EPCs. CD26-mediated SDF-1 inactivation was demonstrated by a decrease in SDF-1-induced actin polymerization in the whole blood of imidapril-treated mice. Imidapril markedly decreased angiographic leakage and CNV size. CD26 inhibition completely blocked the CD26/SDF-1 signaling pathway in vivo and reduced the antiangiogenic effect of imidapril. These results strongly suggest that the antiangiogenic effects of imidapril on laser-induced CNV partially involve the modulation of the CD26/SDF-1 signaling pathway.
MEHTAA,IYERL,PARMARS,et al.Oculohypotensive effect of perindopril in acute and chronic models of glaucoma in rabbits[J].Can J Physiol Pharmacol,2010,88(5):595-600.
We studied the effect of perindopril (1%) on intraocular pressure (IOP) and compared it with the effect of pilocarpine, a therapeutic agent used in experimentally induced acute and chronic models of glaucoma in rabbits. Acute glaucoma was induced by intravenous administration of 5% glucose. Pretreatment with topical perindopril (1%) and pilocarpine (1%) prevented acute rise in IOP induced by intravenous administration of 5% glucose. For inducing chronic ocular hypertension in rabbits, 50 units of freshly prepared alpha-chymotrypsin in 0.1 mL of sterile saline was injected in the posterior chamber of the eye. Perindopril (1%) (35 +/- 1.38 mm Hg to 22.45 +/- 1.42 mm Hg) and pilocarpine (1%) (34.4 +/- 0.81 mm Hg to 20.15 +/- 0.69 mm Hg) produced a significant fall in IOP in these rabbits; pretreatment with indomethacin (prostaglandin synthesis inhibitor) did not affect the IOP-lowering action of perindopril (1%). Perindopril (2.71 x 10(-7) mol/L) and neostigmine (1.49 x 10(-7) mol/L) inhibited true cholinesterase and pseudocholinesterase enzyme activity in blood. The cholinesterase enzyme inhibition by perindopril was comparable with that by neostigmine. In conclusion, our data suggest that perindopril reduced IOP in experimentally induced acute and chronic glaucoma in rabbits. One of the possible mechanisms of perindopril, apart from the inhibition of angiotensin-converting enzyme, may be inhibition of the enzyme cholinesterase.
WANGN,ZHENGZ,JIN HY,et al.Treatment effects of captopril on non-proliferative diabetic retinopathy[J].Chin Med J(Engl),2012,125(2):287-292.
Diabetic retinopathy (DR) is one of the most common complications of diabetes. Angiotensin-converting enzyme inhibitor is thought to play an important role in preventing and treating retinal diseases in animal models of DR. The aim of the present study was to investigate the role of angiotensin-converting enzyme inhibitor (ACEI, captopril) in the treatment of patients with non-proliferative DR.Three hundred and seventeen type 2 diabetic patients (88.05% of participants) without or with mild to moderate non-proliferative retinopathy were randomly divided into captopril group (n = 202) and placebo group (n = 115). All subjects received 24-month follow-up. General clinical examinations, including blood pressure and glycated hemoglobin, as well as comprehensive standardized ophthalmic examinations were performed. Color fundus photography and optical coherence tomography (OCT) were used to grade diabetic retinopathy and detect macular edema respectively.The levels of blood pressure and glycated hemoglobin in the two groups of patients remained within the normal range during the entire follow-up and no significant difference was found between the initial and last visits, suggesting that ACEI drugs play a protective role on the DR patients independent of its anti-blood pressure role. DR classification showed that 169 eyes (83.66%) remained unchanged and the DR grade of 33 eyes (16.34%) increased in captopril group, while 84 eyes (73.04%) remained unchanged and the grade of 31 eyes (26.96%) increased in placebo group (P = 0.024). Captopril treatment improved macular edema in 55.45% eyes, which was significantly higher than the 37.39% improvement in placebo group (P = 0.002). No significant difference was found in the visual acuity between the two groups (P = 0.271).Captopril can improve or delay the development of DR and macular edema, which can be used in the early treatment of DR patients with type 2 diabetic mellitus.
HARINDHANAVUDHIT,MAUERM,KLEINR,et al.Be-nefits of renin-angiotensin blockade on retinopathy in type 1 diabetes vary with glycemic control[J].Diabetes Care,2011,34(8):1838-1842.
Abstract OBJECTIVE: Optimal glycemic control slows diabetic retinopathy (DR) development and progression and is the standard of care for type 1 diabetes. However, these glycemic goals are difficult to achieve and sustain in clinical practice. The Renin Angiotensin System Study (RASS) showed that renin-angiotensin system (RAS) blockade can slow DR progression. In the current study, we evaluate whether glycemic control influenced the benefit of RAS blockade on DR progression in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: We used RASS data to analyze the relationships between two-steps or more DR progression and baseline glycemic levels in 223 normotensive, normoalbuminuric type 1 diabetic patients randomized to receive 5 years of enalapril or losartan compared with placebo. RESULTS: A total of 147 of 223 patients (65.9%) had DR at baseline (47 of 74 patients [63.5%] in placebo and 100 of 149 patients [67.1%] in the combined treatment groups [P = 0.67]). Patients with two-steps or more DR progression had higher baseline A1C than those without progression (9.4 vs. 8.2%, P 7.5% had two-steps or more DR progression compared with 26 of 56 patients (46%) in the placebo group (P = 0.03). CONCLUSIONS: RAS blockade reduces DR progression in normotensive, normoalbuminuric type 1 diabetic patients with A1C >7.5%. Whether this therapy could benefit patients with A1C 7.5% will require long-term studies of much larger cohorts. TRIAL REGISTRATION: ClinicalTrials.gov NCT00143949 .
CHATURVEDIN,SJOLIE AK,STEPHENSON JM,et al.Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes.The EUCLID Study Group.EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus[J].Lancet,1998,351(9095):28-31.
ILIEVAI,OHGAMIK,JIN XH,et al.Captopril suppresses inflammation in endotoxin-induced uveitis in rats[J].Exp Eye Res,2006,83(3):651-657.
Captopril is an inhibitor of angiotensin-converting enzyme (ACE) that is largely used in the treatment of cardiovascular diseases. Several previous studies have demonstrated that captopril exhibits a wide variety of biological activities, including an anti-inflammatory action, on which we focused our attention. The aim of the present study was to investigate the efficacy of captopril on endotoxin induced uveitis (EIU) in rats. We investigated its effect upon cellular infiltration and protein leakage, as well as on the concentration of tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2), monocyte chemoattractant protein-1 (MCP-1) in the anterior chamber. In addition, we checked its effect on activation of nuclear factor kappa B (NF-κB) in iris and ciliary body (ICB) cells in vivo. EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). One hour after the LPS inoculation, either 1 mg/kg, 10 mg/kg or 100 mg/kg captopril were injected intravenously. 24 h later, the aqueous humor was collected from both eyes, and the number of infiltrating cells and protein concentration in the aqueous humor were determined. Levels of TNF-α, PGE2, NO and MCP-1 were determined by enzyme-linked immunosorbent assay. On some eyes, after enucleation, immunohistochemical staining with a monoclonal antibody against activated NF-κB was performed. Captopril treatment significantly decreased the inflammatory cells infiltration, the level of protein, concentrations of TNF-α, PGE2, NO and MCP-1 in the aqueous humor. The number of activated NF-κB-positive cells was lower in ICB of the rats treated with captopril 3 h after the LPS injection. The present results indicate that captopril suppresses the inflammation in EIU by inhibiting the NF-κB-dependent pathway and the subsequent production of pro-inflammatory mediators.
AGARWALR,KRASILNIKOVA AV,RAJA IS,et al.Me-chanisms of angiotensin converting enzyme inhibitor-induced IOP reduction in normotensive rats[J].Eur J Pharmacol,2014,730(1):8-13.
Angiotensin converting enzyme inhibitors (ACEIs) have been shown to lower intraocular pressure (IOP). Since, the ACEIs cause increased tissue prostaglandin levels, we hypothesized that the mechanisms of ACEI-induced IOP reduction have similarity with those of prostaglandin analogs. The present study investigated the involvement of matrix metalloproteinases (MMPs) and cytokine activity modulation as the underlying mechanisms of ACEI-induced ocular hypotension. The IOP lowering effect of single drop of enalaprilat dehydrate 1% was evaluated in rats pretreated with a broad spectrum MMP inhibitor or a cytokine inhibitor. Effect of angiotensin receptor blocker, losartan potassium 2%, was also studied to evaluate involvement of angiotensin II receptor type 1 (AT1) in IOP lowering effect of ACEI. Topical treatment with single drop of enalaprilat resulted in significant IOP reduction in treated eye with mean peak reduction 20.3% at 3h post-instillation. Treatment with losartan resulted in a peak IOP reduction of 13.3%, which was significantly lower than enalaprilat, indicating involvement of mechanisms in addition to AT1 blockade. Pretreatment with a broad spectrum MMP inhibitor or a cytokine inhibitor significantly attenuated the enalprilat-induced IOP reduction with mean peak IOP reduction of 11.2% and 13.6% respectively. The IOP-lowering effect of enalaprilat seems to be attributed to reduced angiotensin II type 1 receptor stimulation and modulation of MMP and cytokines activities.
YAGUCHIS,OGAWAY,SHIMMURAS,et al.Presence and physiologic function of the renin-angiotensin system in mouse lacrimal gland[J].Invest Ophthalmol Vis Sci,2012,53(9):5416-5425.
PURPOSE. To investigate the expression, localization, and physiologic function of renin-angiotensin system (RAS) components in the mouse lacrimal gland. METHODS. Lacrimal glands and cultured lacrimal gland fibroblasts from wild-type (WT) BALB/c (H-2) mice were used. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to determine the expression and localization of the RAS components, prorenin/renin, angiotensin-converting enzyme (ACE), angiotensin II, angiotensin II type 1 receptor (AT1R), and angiotensin II type 2 receptor (AT2R) in the normal mouse lacrimal gland. To examine the change in tear secretion, mice received ARB (AT1R blocker) or AT2R antagonist. Tear secretion was assessed by cotton thread test before and after drug administration. RESULTS. The mRNAs coding for angiotensinogen, prorenin, ACE, and both AT1R and AT2R were found in normal lacrimal gland tissue and cultured lacrimal gland fibroblasts. Prorenin/renin and ACE were identified in myoepithelial cells around ducts and acini and in blood vessels. Angiotensin II, AT1R, and AT2R were observed in the ducts and interstitial fibroblasts. AT1R and AT2R were also localized in blood vessels. All the cultured lacrimal gland fibroblasts expressed angiotensin II, AT1R, and AT2R. Tear secretion increased in mice that received ARB. CONCLUSIONS. The results are consistent with the hypothesis that a tissue-specific RAS is present in the lacrimal gland, and suggest that fibroblasts are one of the cell types playing a role in the tissue RAS. Tissue RAS might be involved in tissue function of regulating tear secretion in the lacrimal gland. 2012 The Association for Research in Vision and Ophthalmology, Inc.
WHITE AJ,CHERUVU SC,SARRISM,et al.Expression of classical components of the renin-angiotensin system in the human eye[J].J Renin Angiotensin Aldosterone Syst,2015,16(1):59-66.
Abstract PURPOSE: The purpose of this study was to determine the relative expression of clinically-relevant components of the renin-angiotensin system (RAS) in the adult human eye. METHODS: We obtained 14 post-mortem enucleated human eyes from patients whom had no history of inflammatory ocular disease nor pre-mortem ocular infection. We determined the gene expression for prorenin, renin, prorenin receptor, angiotensin-converting enzyme, angiotensinogen and angiotensin II Type 1 receptor, on tissue sections and in cultured human primary retinal pigment epithelial and iris pigment epithelial (RPE/IPE) cell lines, using both qualitative and quantitative reverse transcription polymerase chain reaction (RT-PCR). Protein expression was studied using indirect immunofluorescence (IF). RESULTS: Almost all components of the classical RAS were found at high levels, at both the transcript and protein level, in the eyes' uvea and retina; and at lower levels in the cornea, conjunctiva and sclera. There was a much lower level of expression in the reference cultured RPE/IPE cells lines. CONCLUSION: This study describes the distribution of RAS in the normal adult human eye and demonstrates the existence of an independent ocular RAS, with uveal and retinal tissues showing the highest expression of RAS components. These preliminary findings provide scope for examination of additional components of this system in the human eye, as well as possible differential expression under pathological conditions. The Author(s) 2014.
CHOUDHARYR,BODAKHE SH.Olmesartan,an angio-tensin II receptor blocker inhibits the progression of cataract formation in cadmium chloride induced hypertensive albino rats[J].Life Sci,2016,167(15):105-112.
Previously we found that cadmium chloride (CdCl2) exposure substantially elevates hypertension and potentiates cataract formation. In the present study, we investigated the protective effects of olmesartan, an angiotensin II receptor blocker against cataractogenesis in the CdCl2-induced hypertensive animal model. Male Sprague-Dawley albino rats (150 180g) were randomly selected and assigned to four groups (n=6). Among the four groups, one group (normal) received 0.3% carboxymethyl cellulose (10ml/kg/day, p.o.), another group (CdCl2control) received CdCl2(0.5mg/kg/day, i.p.), and remaining two groups received olmesartan at two doses level (2 and 4mg/kg/day, p.o.) concurrently with CdCl2for six consecutive weeks. Blood pressure and cataract formation were examined biweekly, and pathophysiological parameters in serum and eye lenses were evaluated after six weeks of the experimental protocol. The olmesartan treatment significantly restored the blood pressure, lenticular opacity, serum and lens antioxidants (catalase, superoxide dismutase, glutathione peroxidase, and glutathione reduced), and malondialdehyde level. Additionally, it significantly restored the proteins, ions (Na+, K+, and Ca2+), and ATPase pumps activity (Na+K+ATPase and Ca2+ATPase) in the lens as compared to CdCl2control group. The findings demonstrate that olmesartan potentially inhibits the risk of cataract formation in the hypertensive state via restoration of lenticular oxidative stress, ATPase function, and ionic contents in the eye lenses. The results suggest that angiotensin II receptor blockers play an important role to prevent cataract formation in several pathogenic conditions like hypertension, diabetes, and oxidative stress.
An angiotensin-converting enzyme inhi-bitor modulates stromal-derived factor-1 through CD26/dipeptidyl peptidase IV to inhibit laser-induced choroidal neovascularization
Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes.The EUCLID Study Group.EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus
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