Maternotoxicity and fetotoxicity of an angiotensin-converting enzyme inhibitor, enalapril, in rabbits.
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 less than or equal to 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 less than or equal to 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 et 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Minsker
D H
DH
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Bagdon
W J
WJ
MacDonald
J S
JS
Robertson
R T
RT
Bokelman
D L
DL
D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D004656:Enalapril / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects; D005865:Gestational Age; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011817:Rabbits; D013723:Teratogens
D013723:Teratogens; D004656:Enalapril