Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 7/2004

01-07-2004 | Article

Ultrastructural alterations in capillaries of the diabetic hypertensive rat retina: protective effects of ACE inhibition

Authors: A. A. Dosso, E. Rungger-Brändle, P. M. Leuenberger

Published in: Diabetologia | Issue 7/2004

Login to get access

Abstract

Aims/hypothesis

The ACE inhibitor cilazapril was administered to diabetic hypertensive rats to evaluate its ability to influence the development of retinal capillary alterations.

Methods

Normotensive (strain: Wistar Kyoto) and genetically hypertensive (strain: spontaneously hypertensive) rats were rendered diabetic by intravenous injections of streptozotocin. Half of the diabetic animals received cilazapril with their daily food. At 20 weeks of diabetes, endothelial cells, pericytes and extracellular matrix were assessed by ultrastructural morphometry. Each experimental group consisted of seven animals.

Results

Cilazapril normalised systolic arterial pressure in diabetic hypertensive rats (137±2 mm Hg compared with 188±16 mm Hg in non-medicated diabetic hypertensive rats, p<0.001). The number of endothelial intercellular junctions was reduced in untreated diabetic hypertensive rats (0.15±0.05, p<0.02, vs 0.47±0.20 in non-diabetic normotensive rats). In diabetic hypertensive animals treated with cilazapril, this loss was attenuated (0.32±0.16, p<0.05). The significant thickening of the basement membrane observed in the diabetic normotensive (132.8±19.4 nm) and diabetic hypertensive (150.3±20.2 nm) groups was decreased by cilazapril in the diabetic hypertensive group (116.7±11.0 nm, p<0.01), but was unaffected in the normotensive (131.9±17.3 nm) group. No protective effect of the drug was observed in either group on pericytes.

Conclusions/interpretation

Long-term administration of an effective antihypertensive therapy normalises endothelial alterations and basement membrane thickness in diabetic hypertensive conditions, and thus may account for the well-known improvement of the blood-retinal barrier observed during antihypertensive treatment.
Literature
1.
2.
Orchard TJ, Dorman JS, Maser RE et al. (1990) Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes 39:1116–1124CrossRefPubMed
3.
Dwyer MS, Melton LJ, Ballard DJ, Palumbo PJ, Trautmann JC, Chu CP (1985) Incidence of diabetic retinopathy and blindness: a population-based study in Rochester, Minnesota. Diabetes Care 8:316–322CrossRefPubMed
4.
Moss SE, Klein R, Klein BE (1988) The incidence of vision loss in a diabetic population. Ophthalmology 95:1340–1348CrossRef
5.
Porta M, Tomalino MG, Santoro F, Ghigo LD, Cairo M, Aimone M (1995) Diabetic retinopathy as a case of blindness in the province of Turin, north-west Italy, in 1967–1991. Diabetic Med 12:355–361CrossRefPubMed
6.
Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL (1984) The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 102:520–526CrossRef
7.
Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL (1984) The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 102:527–532CrossRefPubMed
8.
Klein R, Klein BEK, Moss SE (1992) Epidemiology of proliferative diabetic retinopathy. Diabetes Care 15:1875–1891CrossRefPubMed
9.
Control and Complications Trial Research Group (DCCT) (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986CrossRef
10.
Teuscher A, Egger M, Herman JB (1989) Diabetes and hypertension: blood pressure in clinical diabetic patients and a control population. Arch Intern Med 149:1942–1945CrossRefPubMed
11.
Klein R, Klein BEK, Le KE, Cruickshanks KJ, Moss SE (1996) The incidence of hypertension in insulin-dependent diabetes. Arch Intern Med 156:622–627CrossRefPubMed
12.
Parving H-H (1991) Impact of blood pressure and antihypertensive treatment on incipient and overt nephropathy, retinopathy, and endothelial permeability in diabetes mellitus. Diabetes Care 14:260–269CrossRefPubMed
13.
Janka HU, Ziegler AG, Valsania P, Warram JH, Krolewski AS (1989) Impact of blood pressure on diabetic retinopathy. Diabetes Metab 15:333–337
14.
Klein BEK, Klein R, Moss SE, Palta M (1995) A cohort study of the relationship of diabetic retinopathy to blood pressure. Arch Ophthalmol 113:601–606CrossRefPubMed
15.
Weidmann P, Böhlen LM, de Courten M (1993) Pathogenesis and treatment of hypertension associated with diabetes mellitus. Am Heart J 125:1498–1513CrossRefPubMed
16.
Parving H-H, Larsen M, Hommel E, Lund-Andersen H (1989) Effect of antihypertensive treatment on blood-retinal barrier permeability to fluorescein in hypertensive Type 1 (insulin-dependent) diabetic patients with background retinopathy. Diabetologia 32:440–444CrossRefPubMed
17.
Gin T, Joon TL, Panagiotopoulos S, Cooper M, Taylor H, Jerums G (1996) Organ specificity of antihypertensive therapy on ocular albumin vascular clearance and albuminuria in the hypertensive diabetic rat. Invest Ophthalmol Vis Sci 37:281–289PubMed
18.
UK Prospective Diabetes Study Group (1998) Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317:713–720CrossRef
19.
Satcher R, Dewey CF Jr, Hartwig JH (1997) Mechanical remodeling of the endothelial surface and actin cytoskeleton induced by fluid flow. Microcirculation 4:439–453CrossRefPubMed
20.
Hansen-Smith F, Greene AS, Cowley AW, Lombard JH (1990) Structural changes during microvascular rarefaction in chronic hypertension. Hypertension 15:922–928CrossRefPubMed
21.
Larsen M, Hommel E, Parving H-H, Lund-Andersen H (1990) Protective effect of captopril on the blood-retinal barrier in normotensive insulin-dependent diabetic patients with nephropathy and background retinopathy. Graefes Arch Clin Exp Ophthalmol 228:505–509CrossRefPubMed
22.
Ottlez A, Bensaoula T (1996) Captopril ameliorates the decreased Na+, K+-ATPase activity in the retina of streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci 37:1633–1641
23.
Chaturvedi N, Sjolie A-K, Stephenson JM, the EUCLID Study Group (1998) Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet 351:28–31CrossRefPubMed
24.
Danser AHJ, van den Dorpel MA, Deinum J et al. (1989) Renin, prorenin, and immunoreactive renin in vitreous fluid from eyes with and without diabetic retinopathy. J Clin Endocrinol Metab 68:160–167CrossRefPubMed
25.
Schalekamp MADH (1993) Renin-angiotensin system components and endothelial proteins as markers of diabetic microvascular disease. Clin Invest 71:S3–S6CrossRef
26.
Ferrari-Dileo G, Davis EB, Anderson DR (1987) Angiotensin binding sites in bovine and human retinal blood vessels. Invest Ophthalmol Vis Sci 28:1747–1751PubMed
27.
Brown SM, Jampol LM (1996) New concepts of regulation of retinal vessel tone. Arch Ophthalmol 114:199–204CrossRefPubMed
28.
Ottlez A, Garcia CA, Eicheberg J, Fox DA (1993) Alterations in retinal Na+, K+-ATPase in diabetes: Streptozotocin-induced and Zucker diabetic fatty rats. Curr Eye Res 12:1111–1121CrossRef
29.
Dosso AA, Leuenberger PM, Rungger-Brändle E (1999) Remodeling of retinal capillaries in the diabetic hypertensive rat. Invest Ophthalmol Vis Sci 40:2405–2410PubMed
30.
Sachs L (1992) Angewandte Statistik. 7th edn. Springer, Berlin Heidelberg
31.
Berka JL, Stubbs AJ, Wang DZ et al. (1995) Renin-containing Muller cells of the retina display endocrine features. Invest Ophthalmol Vis Sci 36:1450–1458PubMed
32.
Kohler K, Wheeler-Schilling T, Jurklies B, Guenther E, Zrenner E (1997) Angiotensin II in the rabbit retina. Vis Neurosci 14:63–71CrossRefPubMed
33.
Murata M, Nakagawa M, Takahashi S (1997) Angiotensinogen mRNA is synthesized locally in rat ocular tissues. Ophthalmologica 211:301–304CrossRefPubMed
34.
Wagner J, Jan Danser AH, Derkx FH et al. (1996) Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system. Br J Ophthalmol 80:159–163CrossRefPubMedPubMedCentral
35.
Gilbert RE, Krumt H, Wilkinson-Berka J, Kelly DJ (2003) The renin-angiotensin system and the long-term complications of diabetes: pathophysiological and therapeutic considerations. Diabet Med 20:607–621CrossRefPubMed
36.
Sinclair SH, Grunwald JE, Riva C, Braunstein SL, Nichols CW, Schwartz S (1982) Retinal vascular autoregulation in diabetes mellitus. Ophthalmology 89:748–750CrossRefPubMed
37.
Ottlez A, Bensaoula T, Eichberg J, Peterson RG (1996) Angiotensin-converting enzyme activity in retinas of streptozotocin-induced and zucker diabetic rats. Invest Ophthalmol Vis Sci 37:2157–2164
38.
Patel V, Rassam SMB, Chen HC, Jones M, Kohner EM (1998) Effect of angiotensin-converting enzyme inhibition with perindopril and b-blockade with atenolol on retinal blood flow in hypertensive diabetic subjects. Metabolism 47:28–33CrossRefPubMed
39.
Luetscher JA, Kreamer FB, Wilson DM (1989) Prorenin and vascular complications of diabetes. Am J Hypertens 2:382–386CrossRefPubMed
40.
Gupta S, Sussman I, MacArthur CS, Tornheim K, Cohen RA, Ruderman NB (1992) Endothelium-dependent inhibition of Na+, K+-ATPase activity in rabbit aorta by hyperglycemia. J Clin Invest 90:727–732CrossRefPubMedPubMedCentral
41.
Bui BV, Armitage JA, Tolcos M, Cooper ME, Vingrys AJ (2003) ACE inhibition salvages the visual loss caused by diabetes. Diabetologia 46:401–408CrossRefPubMed
42.
Gilbert RE, Vranes D, Berka JL et al. (1998) Vascular endothelial growth factor and its receptors in control and diabetic rats eyes. Lab Invest 78:1017–1027PubMed
43.
Gilbert RE, Kelly DJ, Cox AJ et al. (2000) Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes. Diabetologia 43:1360–1367CrossRefPubMed
44.
Moravski CJ, Skinner SL, Stubbs AJ et al. (2003) The renin-angiotensin system influences ocular endothelial cell proliferation in diabetes. Am J Pathol 162:151–160CrossRefPubMedPubMedCentral
45.
Blobe CB, Schiemann WP, Lodish HF (2000) Role of transforming growth factor-beta in human disease. N Engl J Med 342:1350–1360CrossRefPubMed
46.
Ziyadeh FN, Sharma K, Ericksen M, Wolf G (1994) Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta. J Clin Invest 93:536–542CrossRefPubMedPubMedCentral
47.
Kagami S, Border WA, Miller DE, Noble NA (1994) Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest 93:2431–2437CrossRefPubMedPubMedCentral
48.
Wolf G, Haberstroh U, Neilson EG (1992) Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol 140:95–107PubMedPubMedCentral
49.
Ray PE, Bruggeman LA, Horikoshi S, Aguilera G, Klotman PE (1994) Angiotensin II stimulates human fetal mesangial cell proliferation and fibronectin biosynthesis by binding to AT1 receptors. Kidney Int 45:177–184CrossRefPubMed
50.
Singh R, Alavi N, Singh AK, Leehey DJ (1999) Role of angiotensin II in glucose-induced inhibition of mesangial matrix degradation. Diabetes 48:2066–2073CrossRefPubMed
51.
Nakamura T, Takahashi T, Fukui M et al. (1995) Enalapril attenuates increased gene expression of extracellular matrix components in diabetic rats. J Am Soc Nephrol 5:1492–1497PubMed
52.
Kalender B, Ozturk M, Tuncdemir M et al. (2002) Renoprotective effects of valsartan and enalapril in STZ-induced diabetes in rats. Acta Histochem 104:123–130CrossRefPubMed
53.
Volpini RA, da Silva CG, Costa RS, Coimbra TM (2003) Effect of enalapril and losartan on the events that precede diabetic nephropathy in rats. Diabetes Metab Res Rev 19:43–51CrossRefPubMed
54.
Zhang J-Z, Gao L, Widness M, Xi X, Kern TS (2003) Captopril inhibits glucose accumulation in retinal cells in diabetes. Invest Ophthalmol Vis Sci 44:4001–4005CrossRefPubMed
Metadata
Title
Ultrastructural alterations in capillaries of the diabetic hypertensive rat retina: protective effects of ACE inhibition
Authors
A. A. Dosso
E. Rungger-Brändle
P. M. Leuenberger
Publication date
01-07-2004
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 7/2004
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1442-3

Other articles of this Issue 7/2004

Diabetologia 7/2004 Go to the issue

Comment

—to: Hales CN, Ozanne SE (2003) For Debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure. Diabetologia 46:1013–1019

Article

Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial

Article

Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes

Author’s Reply

Reply to Comment on: Hales CN, Ozanne SE (2003) For Debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure

For Debate

Towards worldwide standardisation of HbA1c determination

Short Communication

Serum adiponectin levels predict the effect of short-term dietary interventions on insulin sensitivity in humans
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits