Effect of Captopril on Uterine Blood Flow and Prostaglandin E Synthesis in the Pregnant Rabbit

Abstract

A B S T R A C T Captopril, 5 mg/kg, administered to pregnant rabbits caused a reduction in mean arterial pressure (MAP) from 106±2 to 87±2 mmHg (P < 0.01) without change in cardiac output or renal blood flow.Uterine blood flow fell from 31.9±2.5 to 21.3±3.4 ml/ min (P < 0.01) as uterine vein prostaglandin E series level (PGE) decreased from 127±23 ng/ml to 26±8 ng/ml (P < 0.01). Saralasin also caused a reduction in MAP from 110±5 to 92±4.3 (P < 0.01), a reduction in uterine blood flow from 28.8±1.6 to 21.8±1.7 ml/ min (P < 0.01) as uterine vein PGE decreased from 121.3±14.4 to 63.5±14.2 ng/ml (P < 0.01). Plasma renin activity (PRA) was higher in the uterine vein, 11±3 ng/ml per h, than peripheral vein, 6±1.6 ng/ml per h, (P < 0.05), before Captopril and rose in the uterine vein to 90±19 ng/ml per h (P < 0.01) as peripheral vein PRA rose to 62±15 ng/ml per h (P <0.05) after Captopril. After saralasin uterine vein PRA rose from 4.6±1.5 to 14.8±6.3 ng/ml per h (P < 0.05) and peripheral vein PRA rose from 3.7±1 to 6.5±2.1 (P < 0.05).Reducing MAP with MgSO, from 98±4 to 70±2 (P < 0.01) caused a significant fall in cardiac output from 695±33 to 588±49 (P < 0.01) without change in renal or uterine blood flow. Uterine vein PGE concentration also did not change significantly following MgSO4; 80±22 ng/ml before and 60±27 ng/ml (NS) during the administration of MgSO4.Chronic administration of Captopril in doses of either 2.5 or 5.0 mg/kg per d from the 15th d of gestation caused an 86% fetal mortality at the lower and a 92% fetal mortality at the higher dose of the drug.These experiments point to the importance of uterine PGE synthesis in maintenance of uterine blood flow and fetal survival during pregnancy and suggest that uterine PGE synthesis is dependent upon angioAddress reprint requests to Dr. T.

Gonadotropin stimulates ovarian renin-angiotensin system in the rabbit.

“…Several classes of potent and specific nonpeptide inhibitors have been synthesized in an effort to produce active ACE inhibitors that could be useful as antihypertensive agents (34). Captopril is thought to bind the active site of ACE in a manner analogous to endogenous substrates, and has been widely used in experiments designed to define the biological function of ACE (35)(36)(37)(38). The addition of captopril to the perfusate did not inhibit hCG-induced ovulation, despite significant reductions in both the intrafollicular Ang II content and the secretion rate ofAng II in ovaries perfused with hCG.…”

Maternal Placental Blood Flow Is Reduced in Proportion to Reduction in Uterine Driving Pressure

“…However, Venuto et al (3) claimed that uteroplacental blood flow is autoregulated between 60 and 140 mm Hg in anesthetized rabbits studied under a variety of conditions. This group of investigators also reported that there is a loss of autoregulation of placental blood flow in the anesthetized rabbit after administration of an inhibitor of the renin-angiotensin system (4).…”

The effect of enalapril (MK421), an angiotensin converting enzyme inhibitor, on the conscious pregnant ewe and her foetus

“…Blockade of the maternal renin-angiotensin system in the conscious pregnant sheep, whether with the receptor blocker, Saralasin (Broughton Pipkin & O'Brien, 1978) or captopril (Broughton Pipkin et al, 1982) results in a fall ofmaternal blood pressure. However, whereas the effects of Saralasin are short-lived, and apparently not transmitted to the foetus, the maternal administration of captopril is associated with a rapid foetal hypotension, and a much increased stillbirth rate in both sheep and rabbits (Broughton Pipkin et al, 1982;Ferris & Weir, 1983). Its administration to pregnant guineapigs was associated with a marked fall in foetoplacental ACE activity (Davidson et al, 1981).…”

“…The active form (enaprilic acid, MK422) is a potent ACE inhibitor, with a long duration of action (Ulm, 1983). The administration of captopril was found to be associated with a marked increase in the perinatal mortality rate in both sheep and rabbits (Broughton Pipkin et al, 1982;Ferris & Weir, 1983). Because of the differences between the two classes of ACE inhibitor, we felt it would be of interest to study the effects of MK421/422 in sheep pregnancy, under the same conditions as those in which we had originally studied captopril (Broughton Pipkin et al, 1982).…”