Histostereological nephroteratogenic effects of enalapril on the fetal kidneys in albino rats (rattus norvegicus)

Abstract

The existing literature has shown that enalapril, a widely prescribed antihypertensive due to its monotherapeutic success and its cost effectiveness, is nephroteratogenic when applied in-utero. However, data on its teratogenic histostereological effects on the developing fetal kidneys is generally lacking. At the same time data on whether or not its teratogenic effects on the fetal kidneys are time and dose dependent is also scarce. In carrying out the study, a static-group controlled-experimental study design was adopted where a pure breed of 30 sexually mature albino rat dams weighing between 150-250g were used. These 30 dams were assigned into two study groups of 3 control and 27 experimental. To evaluate the most critical period, the experimental group was subdivided into three study groups of 9 rats each of Low, medium and high Dose Enalapril Groups namely; [LDEG-0.5mg/kg/bw], [MDEG-1mg/kg/Bw], and [HDEG-2mg/kg/bw] respectively. To evaluate the most critical period, the 9 rats in each of the three dose groups were further sub-divided into three sub groups according to the time of exposure as follows; 3 rats for trimester one( TM1),3rats for trimester two (TM2,) and 3 rats for trimester three (TM3). All rats were fed with standard rodent pellets from Unga feeds and water ad-libitum, while those in the experimental group in addition received enalapril treatment as per their groups of study. All rats were humanely sacrificed at GD20 then 3 fetuses with the lowest, median and highest weight from each rats selected and their kidneys harvested, weighed and processed for histo-morphological and stereological analysis. Data was collected using tally sheets, analyzed using SPSS version 23.0 (SPSS Inc., Chicago, IL). One-way Analysis of Variance (ANOVA) followed by Tukey’s post hoc multiple comparison tests were done and results expressed as mean ± standard error of the mean (SEM) for all values. All results whose p<0.05 were considered to be statistically significant. Findings were presented in form of bar charts and tables. This study elucidated that prenatal exposure to enalapril results to varied teratogenic outcomes including increased embryo-lethality, increased intrauterine fetal resorptions, fetal congenital abnormalities, and reduced mean litter sizes; significant reduction in gross kidney volumes, reduction in cortical layer thickness, widened capsular space with glomerular hypertrophy. In conclusion, when enalapril is administered in the doses of between 1mg/kg/BW and 2mg/kg/BW during pregnancy are teratogenic to the developing fetal kidney particularly during second and third trimesters (TM2) and (TM3) respectively. Teratogenic effects in trimester one (TM1) occurred only in high doses. The most vulnerable window period and critical dose for enalapril teratogenicity was established to be TM2 at 2mg/kg/BW respectively. The study recommends that maternal enalapril should be avoided particularly in TM2, TM3 and in TM1 in doses of 2mg/kg/BW and alternative antihypertensive sought. Further studies are recommended in higher non-human primates like monkeys and gorillas.