© 1990 Oxford University Press
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Maternotoxicity and Fetotoxicity of an Angiotensin-Converting Enzyme Inhibitor, Enalapril, in Rabbits
Merck Sharp & Dohme Research Laboratories West Point, Pennsylvania, 19486
Received March 15, 1989; accepted September 22, 1989
Maternotoxicity and Fetotoxicity of an Angiotensin-Converting Enzyme Inhibitor, Enalapril, in Rabbits. MINSKER, D. H., BAGDON, W. J., MACDONALD, J. S., ROBERTSON, R. T., AND BOKELMAN, D. L. (1990). Fundam. Appl. Toxicol 14, 461–470. When enalapril, an angiotensin-converting enzyme (ACE) inhibitor, was orally administered to inseminated rabbits at dosages of 0.1 to 30 mg/kg/day for 13 days in a range-finding study, nephrotoxicity, as measured by elevated serum urea nitrogen concentrations, occurred at 1 mg/kg/day and higher dosages and significant (p 
0.05) increases in fetal wastage were observed at dosages as low as 3 mg/kg/day. Saline supplementation during treatment prevented this rise in urea nitrogen. Fetal wastage was significantly (p 0.05) increased in the absence of maternotoxicity when saline-supplemented females were treated with enalapril at 30 mg/kg/day. A developmental toxicity study of enalapril in saline-supplemented rabbits produced no evidence of teratogenicity at 3, 10, and 30 mg/kg/ day. The period of sensitivity of fetuses to the toxic effects of enalapril was found to be limited to middle-to-late gestation (Gestational Days 14-27). A single oral dose of enalapril (30 mg/kg) on Day 26 of gestation resulted in 100% fetal deaths. On the basis of the work done by Broughton Pipkin el al. [1982, J. Physiol. (London) 323, 415–422] and Broughton Pipkin and Wallace (1986, Brit. J. Pharmacol 87, 533–542), which demonstrated that the sheep fetus becomes markedly hypotensive when the dam is treated with captopril or enalapril during late pregnancy, we believe that the observed fetotoxicity of enalapril in rabbits is also due to fetal hypotension. On the basis of published evidence indicating that the renin-angiotensin system in rabbits and in humans is not developed until middle-to-late gestation, we believe our results support the premise that incidental exposure to enalapril early in human pregnancy is unlikely to be associated with an increased risk of fetotoxicity. However, our results and those cited above demonstrate that ACE inhibitors are fetotoxic in late gestation in rabbits and sheep, and should be given in pregnancy only if the potential benefit justifies the potential risk to the fetus.