Enalaprilat as a new means of preventing the development of retinopathy of prematurity

Abstract

In a rat model of experimental retinopathy of prematurity (ROP), the safety of enalaprilat and its effect on the level of angiotensin-converting enzyme (ACE) and angiotensin-II (AT-II) in the vitreous body and retina were investigated. The study was performed on 136 newborn Wistar rat pups divided into 2 groups: group A — experimental (animals with ROP, n=64) and group B — control (n=72). Each group was further divided into 2 subgroups: A0 and B0 (n=32 and n=36, respectively) — animals that did not receive injections of enalaprilat, and A1 and B1 (n=32 and n=36, respectively) — animals treated with daily intraperitoneal (i.p.) injections of enalaprilat (0.6 mg/kg of body weight). This treatment started on day 2 and lasted either to day 7 or to day 14 in accordance with the therapeutic scheme. Animals were taken out of the experiment on day 7 and day 14. In samples of the vitreous body and retina, the content of ACE and AT-II was determined by enzyme immunoassay. On day 7 in subgroups A1 and B1 the levels of ACE and AT-II in the vitreous did not differ, while on day 14 were lower than in subgroups A0 and B0, respectively. Changes in the parameters studied in the retina were somewhat different from those found in the vitreous body. On the seventh day, the level of ACE in the retina of animals of subgroup B1 did not differ significantly from subgroup B0, and in subgroup A1 it was increased compared to subgroup A0. On day 14, its significant decrease was noted in subgroups A1 and B1 as compared with subgroups A0 and B0. At the same time, the level of AT-II in the retina of rat pups of subgroup B1 was lower than in subgroup B0, both on day 7 and day 14. On day 7, the concentration of AT-II, as well as the concentration of ACE, increased in subgroup A1 as compared to subgroup A0. On day 14, this parameter in subgroup A1 was significantly lower as compared to subgroup A0, but significantly higher than in subgroup B1. It should be noted that i.p. injections of enalaprilat, increased a death rate of animals of both groups. The use of enalaprilat, starting from the preclinical period of the ROP development, led to a decrease in the activity of the renin-angiotensin system (RAS) in ROP animals at the onset of retinopathy in the experimental model used. This opens up prospects for considering enalaprilat as a means of preventing the development of this pathology; however, the recognized high toxicity of the drug requires further studies and correction of the timing of its administration and dosage in order to achieve a balance of efficacy and safety of use in order to prevent the development of ROP in children.