Retinal and Choroidal Vasculature in Rats with Spontaneous Diabetes Type 2 Treated with the Angiotensin-Converting Enzyme Inhibitor Cilazapril: Corrosion Cast and Electron-Microscopic Study

Abstract

The long-term effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on retinal and choroidal circulation in rats with spontaneous diabetes type 2 were assessed by corrosion casts, scanning electron microscopy (SEM) and transmission electron microscopy. One group of 20 male Otsuka Long-Evans Tokushima Fatty (OLETF) rats was treated with 10 mg/kg/day of cilazapril from 4 to 64 weeks of age, and 20 other OLETF rats received no treatment. A third group, 20 male Long-Evans Tokushima Otsuka (LETO) rats, served as age-matched controls. At regular intervals, the rats were weighed, and their blood glucose was measured. Before the experiment, their systolic blood pressure and total cholesterol level were determined. At 64 weeks of age, the OLETF rats weighed significantly less than the cilazapril-treated OLETF and the LETO rats (p < 0.0001). At the same age, 100% of the untreated OLETF rats had bilateral cataracts, while the lens was clear and no fundus abnormality was detected in the cilazapril-treated OLETF rats and the LETO rats. Cilazapril lowered systolic blood pressure to a nearly normal level, significantly prevented the increase in blood sugar and inhibited the increase in serum cholesterol in the OLETF rats throughout the treatment. In the 64-week-old OLETF rats without treatment, corrosion cast and SEM revealed diabetic retinal and choroidal vascular changes: tortuosity of the vessels, variations in caliber, narrowing of arteries, arterio-arteriolar anastomoses and hairpin loop formation in precapillary arterioles, sparse collecting venules in the choroid and marked capillary changes such as caliber irregularity, narrowing, tortuosity, loop formation and decreased capillaries, outpouching and microaneurysms. In the cilazapril-treated OLETF rats, these changes were markedly decreased to the level seen in the LETO rats, in which the retinal and choroidal blood vessels had a definite and fairly constant pattern and the capillaries were more regularly and densely arranged and had a remarkably uniform caliber. Our results show that the long-term administration of cilazapril before or from the initial onset significantly prevented the increase in blood sugar and inhibited the increases in serum cholesterol in OLETF rats throughout the treatment, lowered systolic arterial pressure to a nearly normal level and prevented diabetic ocular complications. The effects of cilazapril on the diabetic retinal and choroidal vasculature are described for the first time. SEM of corrosion casts is a valuable and easy technique for showing precisely and three-dimensionally the effects of some drugs on the vasculature.

VEGF-induced choroidal damage in a murine model of retinal neovascularisation

“…There is thus no evidence for choroidal neovascularisation (CNV) as observed, for example, in macular degeneration 20. However, capillary constrictions and dropout appear similar between the two beds,14 17 21 22 as does tortuousity within the major vessels 21 22…”

Inhibition of Experimental Choroidal Neovascularization by Irsogladine, an Anti-Gastric Ulcer Agent

“…The corrosion cast/SEM method has been used to study the microangioarchitecture in various organs and tissues under various pathological conditions [24][25][26][27][28][29]. Using the corrosion cast method, many authors have described the effects of laser photocoagulation in the choroid [30,31] and experimental CNV [5,[32][33][34][35].…”

Change in peripapillary and macular choroidal thickness change in children with type 1 diabetes mellitus without visual impairment or diabetic retinopathy

“…Cholesterol is an important metabolic factor to posterior CT in children with T1DM. Studies in type 2 diabetic rat models have shown that cholesterol may be associated with vascular tortuosity, changes in the vascular diameter and arterial stenosis due to diabetes (Bhutto et al 2002). It is likely that in the eyes of children with diabetes, high cholesterol may cause choroidal vasculopathy and thus changes in the CT. Serum cholesterol concentration is a factor that can be controlled unlike the other two factors.…”