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Maternal and uteroplacental hemodynamic effects of chronic captopril in the hypertensive, term-pregnant rat
Low-dose aspirin, vascular reactivity, and preeclampsia
Volume 163 Number 6, Part 1
8.
9. 10.
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manifestation of pregnancy-induced hypertension. Circulation 1987;75:956. Goodman RP, Killam AP, Brash AR, Branch RA. Prostacyclin production during pregnancy: comparison of production during normal pregnancy and pregnancy complicated by hypertension. A~I j OBSTET GY:-iECOL 1982;142:817. Walsh SW. Preeclampsia: an imbalance in placental prostacyclin and thromboxane production. AM j OBSTET Gy:-iECOL 1985;152:335. Fitzgerald Dj, Mayo G, Catella F, Entmann S, Fitzgerald GA. Increased thromboxane biosynthesis in normal pregnancy is mainly derived from platelets. AM j OBSTET Gy:-;ECOL 1987;157:325. Beaufils M, Uzan S, Donsimoni R, Colau jC. Prevention of pre-eclampsia by early anti platelet therapy. Lancet 1985;1:840. Wallenburg H CS, Dekker GA, Makovitz jW, Rotmans P. Low-dose aspirin prevents pregnancy-induced hypertension and preeclampsia in angiotensin-sensitive primigravidae. Lancet 1986; 1: I. Schiff E, Peleg E, Goldenberg M, et al. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. N Engl j Med 1989;321 :351. Spitz B, Magness RR, Cox SM, Brown CEL, Rosenfeld CR, Gant NF. Low-dose aspirin. I. Effect on angiotensin II pressor responses and blood prostaglandin concentra-
15.
16.
17. 18. 19. 20. 21.
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tions in pregnant women sensitive to angiotensin II. AM j OBSTET GYNECOL 1988; 159: 1035. Sanchez-Ramos L, O'Sullivan M, Garrido-CalderonJ. Effect oflow-dose aspirin on angiotensin II pressor response in human pregnancy. AM j OBSTET GYNECOL 1987;156: 193. Caruso A, Ferrazzani S, DeCarolis S, Lanzone A, Mancuso S. Effects of low-dose aspirin on vascular sensitivity to angiotensin II and on 24 hours arterial blood pressure in pregnancy. Clin Exp Hypertens Hypertens Pregnancy 1988; B7:171. Cunningham FG, MacDonald PC, Gant NF. Hypertensive disorders in pregnancy. In: Williams' obstetrics. 18th ed. Norwalk, Connecticut: Appleton & Lange, 1989:653. Sibai BM, Mirro R, Chesney CM, Leffler C. Low-dose aspirin in pregnancy. Obstet Gynecol 1989;74:551. Friedman SA. Preeclampsia: a review of the role of prostaglandins. Obstet Gynecol 1988;71:122. Chesley LC. Hypertension in pregnancy: definitions, familial factor, and remote prognosis. Kidney Int 1980; 18 (suppl):234. Sutherland A, Cooper DW, Howie PW, Liston WA, MacGillivray I. The incidence of severe pre-eclampsia amongst mothers and mothers-in-law of pre-eclamptics and controls. Br j Obstet GynaecoI1981;88:785. Cooper DW, Liston WA. Genetic control of severe preeclampsia. j Med Genet 1979; 16:409.
Maternal and uteroplacental hemodynamic effects of chronic captopril in the hypertensive, term-pregnant rat William C. Mabie, MD, Robert A. Ahokas, PhD, and Baha M. Sibai, MD Memphis, Tennessee The chronic effects of captopril on maternal hemodynamics and organ perfusion were investigated in 10 untreated and 10 captopril-treated pregnant spontaneously hypertensive rats by means of the radioactive-labeled microsphere technique. The normal decrease in blood pressure during gestation was prevented by reduction of litter size to two conceptuses on day 7 of gestation. Captopril (=10 mg/kg/day) or drug vehicle (50% ethyl alcohol) was administered intraperitoneally by an osmotic pump from day 7 to 21. At term mean arterial pressure was 23% lower in the captopril-treated group as the result of a 29% decrease in total peripheral resistance without a significant change in cardiac output. The decrease in total peripheral resistance was primarily caused by a decline in splanchnic and skin resistances. Maternal organ and uteroplacental perfusion were not significantly altered. We conclude that administration of captopril during the last 2 weeks of pregnancy in the hypertensive rat effectively lowers maternal blood pressure without adverse effects on organ and uteroplacental perfusion. (AM J OSSlEl GVNECOL 1990;163:1861-7.)
Key words: Captopril, total peripheral resistance, placental perfusion, spontaneously hypertensive rat
Frorn the Division of Maternal-Fetal Medicine, Departrnent of Obstetrics and Gynecology, University of Tennessee-Mernphis. Presented at the Thirty-seventh Annual Meeting of the Society for Gynecologic [nvestigation, St. Louis, Missouri, March 21-24,1990. Reprint requests: Williarn C. Mabie, MD, Departrnent of Obstetrics and Gynecology, Universif.V of Tennessee-Mernphis, 853 jefferson Ave., Mernphis, TN 38103.
6/6/24774
In 1981 captopril was approved by the Food and Drug Administration for use as an antihypertensive agent in the United States. I Since then two other angiotensin-converting enzyme inhibitors, enalapril and lisinopril, have been approved and at least 14 other such inhibitors are under development. 2 Because of 1861
1862 Mabie, Ahokas, and Sibai
their efficacy and low side-effect profile angiotensinconverting enzyme inhibitors are widely used as firstline therapy for hypertension. The mechanism of action of the angiotensinconverting enzyme inhibitors is not completely understood, but it is thought that they induce vasodilatation by inhibiting angiotensin-converting enzyme, the enzyme that converts angiotensin I to angiotensin II. In addition to being a potent vasoconstrictor, angiotensin II stimulates aldosterone secretion and increases sympathetic outflow centrally. Because angiotensinconverting enzyme is identical to kininase II, which inactivates bradykinin, an additional antihypertensive effect may result from increased bradykinin levels. Finally, certain angiotensin-converting enzyme inhibitors increase synthesis of the vasodilating prostaglandins E2 and 12 • 2 •4 Accumulating evidence indicates that the major site of angiotensin II production is not in blood but in tissues (e.g., vascular, cardiac, renal, and brain). The decrease in blood pressure correlates better with the degree of inhibition of the vascular tissue reninangiotensin system than with the circulating reninangiotensin system. 2 As with any antihypertensive drug, the primary concerns about the use of captopril in pregnancy are the possible adverse effects on placental perfusion and the risk of congenital malformations. Captopril caused fetal death in rabbits, apparently by reduction of uteroplacental perfusion.' It caused maternal and fetal hypotension and stillbirth in sheep.6 Although results are conflicting, congenital malformations and other fetal complications have been associated with its use in human pregnancy.7-9 Therefore it has been recommended that captopril not be used during pregnancy.8. 10 The spontaneously hypertensive rat is widely accepted as a model of human essential hypertension. However, even in this genetically hypertensive animal, pregnancy has a profound blood pressure-lowering effect. During the last week of gestation blood pressure progressively decreases and usually reaches normotensive levels by term. We have recently shown that the magnitude of the decrease in blood pressure in the pregnant spontaneously hypertensive rat is directly proportional to litter size." The resistances of virtually all the maternal organ vascular beds, including the uterus and placentas, at term are inversely related to litter size. Thus reducing litter size to one or two conceptuses shortly after implantation prevents the normal decrease in blood pressure, producing a model of essential hypertension during pregnancy. The purpose of this study was to evaluate the effects oflowering maternal blood pressure with captopril during the last 2 weeks of pregnancy on maternal and utero placental hemodynamics at term in the hypertensive, pregnant rat.
December 1990 Am J Obstet Gynecol
Material and methods
This research conforms with the "Guiding Principles in the Care and Use of Laboratory Animals" approved by the Council of the American Physiological Society and with federal laws and regulations. The protocol used was approved by the University of Tennessee, Memphis, Animal Care and Use Committee. Virgin female spontaneously hypertensive rats (10 to 12 weeks of age) were purchased from Harlan/Sprague-Dawley, Inc. (Indianapolis). They were housed four per cage in a temperature-controlled room (23 0 ± 10 C) with lights on from 7 AM to 7 PM and were fed Purina Laboratory Rodent Chow (Ralston Purina, St. Louis) as desired with tap water to drink. For breeding, the females were housed 1 : 1 with mature male spontaneously hypertensive rats. Vaginal smears were checked daily in the morning for the presence of spermatozoa. The day vaginal smears were sperm positive was designated day 0 of pregnancy and the timed pregnant rats were housed singly throughout pregnancy. Systolic blood pressure was measured by tail-cuff plethysmography (IITC, Inc., Woodland Hills, Calif.) and was monitored every other day throughout gestation. For these measurements the rats were prewarmed to 300 C for 15 to 20 minutes in an incubator. They were then placed in a Plexiglas restraining cage and an inflatable cuff with a photoelectric sensor was placed around the base of the tail. The cuff was then inflated to a pressure of 250 mm Hg. The pressure was gradually released until a pulse was detected (systolic blood pressure). The mean of 3 to 5 determinations was recorded for each day. On day 7 of gestation a laparotomy was performed with the rat under light methoxyflurane anesthesia and litter size was reduced to two (one in each uterine horn) by aspiration of embryos through small incisions in the anti mesometrial uterine wall. The uterine incisions were then closed with sutures. A sterile osmotic minipump (model 2001, Alza Corp., Palo Alto, Calif.) filled with either a sterile solution of captopril (200 mg/ml) or drug vehicle (50% ethyl alcohol) was placed in the abdominal cavity to administer the contents intra peritoneally. Infusion rate was 0.5 f,Ll/hr (2.4 mg of captopril per day). This rate of infusion resulted in a dosage of -10 to 12 mg/kg/day. The abdominal incisions were closed, and the rats were injected with penicillin G (30,000 U /kg intramuscularly) and returned to their cages for the duration of pregnancy. On postmating day 21 (the day before delivery), mean arterial pressure, cardiac output, and organ blood flows were measured with the radioactive-labeled microsphere technique described previously.12-14 Mean arterial pressure, cardiac output, and organ blood flows
Captopril in pregnant rat
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Postmatlng Day Fig. 1. Changes in systolic blood pressure during gestation in control and captopril-treated spontaneously hypertensive rats. Osmotic pump for intraperitoneal drug administration was implal1led on dav 7. Data are plotted as mean ± SEM. A.lterisk indicates significant difference between groups (P < 0.05).
were measured after a minimum 2-hour anesthesia recovery period. The data were expressed as the mean ± SEM. Systolic blood pressure data was analyzed by two-way analysis of variance. Student t test was used for comparison of mean arterial pressure, cardiac output, total peripheral resistance, organ flows, and organ vascular resistances between groups. The 95% confidence level was accepted as statistically significant for all analyses. Results
Fig. I depicts the mean systolic blood pressure measured on alternate days during gestation for the untreated and captopril-treated rats. On day 0, mean systolic blood pressure in the two groups was not different. On day 7, the day treatment was started, mean systolic blood pressure was 186 ± 3 mm Hg and 185 ± 4 mm Hg in the untreated and captopril-treated groups, respectively. Captopril produced a significant reduction in mean systolic blood pressure that persisted throughout gestation beginning on the first day or two after pump implantation. On day 21, mean systolic blood pressure was 186 ± 6 mm Hg and 143 ± 2 mm Hg in the untreated and captopril-treated rats, respectively. Table I shows the total body, maternal organ, and fetal and placental weights of the untreated and
captopril-treated rats. Net maternal weight, but not mean fetal or placental weight, was significantly lower in the captopril-treated compared with the untreated rats. This was primarily a result of lower carcass, skin, and liver weights. Captopril treatment may have resulted in reduced food consumption, although this factor was not measured. Nine of the control rats had two fetuses at term compared with six of the captopriltreated rats, a nonsignificant difference. One rat in the control group and four in the captopril-treated group aborted one conceptus and carried one to term. There was no decaying tissue found in the uteri of the rats with only one fetus that would suggest recent fetal death, and all living fetuses appeared structurally normal. There was no significant difference in mean fetal or placental weight between the two groups. The effects of captopril on maternal hemodynamics at term are summarized in Fig. 2. Mean arterial pressure was 23% lower in the captopril-treated group than in the control group (130.2 ± 4.7 mm Hg vs 169.0 ± 3.6 mm Hg, p < 0.01). Maternal cardiac index was unchanged but total peripheral resistance of the captopril-treated rats was 29% lower than that of the untreated rats (4.68 ± 0.38 vs 3.33 ± 0.30 mm Hg/mllminl 100/gm, p < 0.02). There was a nearly significant increase (p = 0.(6) in apparent lung blood flow (1.6 ± 0.3% vs 5.2 ± 1.8%
1864
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December 1990 Am.J Obstet Gvnecol
Mean Arterial Pressure 2~~------------------~
Cardiac Index
Total Peripheral Resistance
f Control
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Fig. 2. Mean arterial pressure, cardiac index, and total peripheral resistance at term in 10 control and 10 captopril-treated (= 10 mg/kg/day) spontaneously hypertensive rats.
Table I. Total body, maternal organ, and fetal and placental weights of untreated and captopril-treated rats COlltrol
Total body weight, day 0 (gm) Total body weight, day 21 (gm) Net maternal weight, day 21 (gm) Carcass (gm) Skin (gm) Brain (gm) Heart (gm) Lungs (gm) Stomach (gm) Small intestine (gm) Large intestine (gm) Liver (gm) Spleen (gm) Pancreas (gm) Kidneys (gm) Adrenal glands (gm) Ovaries (gm) Uterus (gIll) Litter size Mean fetal weight (gm) Mean placental weight (gm)
Cal)topril
197.2 ± 3.5 251.2 ± 7.0 207.8 ± 6.0 142.33 ± 4.74 34.45 ± 0.92 1.82 ± 0.03 1.06 ± 0.04 1.21 ± 0.04 1.30 ± 0.05 4.95±0.18 :1.32 ± 0.11 11.07 ± O.:H 0.45 ± 0.18 0.67 ± 0.07 1.56 ± 0.17 0.08 ± 0.01 0.11 ± OJ)I 2.1:') ± 0.12 19/20
4.72 ± 0.22 0.58 ± 0.03
of cardiac output) in the untreated and captopriltreated groups, respectively. This may have been a result of the opening of systemic arteriovenous shunts by captopril. Fig. 3 illustrates the splanchnic, skin, and remaining carcass blood flows and vascular resistances of untreated and captopril-treated rats. Captopril produced significant reductions in splanchnic and skin vascular resistances but had no significant affect on splanchnic, skin, or carcass blood flows. Fig. 4 summarizes the cardiac, renal, adrenal, and reproductive organ blood flows and resistances in untreated and captopril-treated rats. There were no statistically significant differences between groups in either blood flow or resistance values.
211.0 263.6 189.6 129.63 32.09 1.80 0.9:) 1.17 1.25 4.81 3.21 10.1:) 0.48 0.62 1.53 0.08 0.11 1.71
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7.0 5.0 :1.5 2.49 0.72 0.03 0.06 0.03 0.03 0.19 0.11 0.28 0.03 0.05 0.05 0.01 0.01 0.11
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Comment
The traditional concept of the renin-angiotensin system is that of a circulation-borne endocrine system in which angiotensinogen is produced by the liver, renin by the kidney, and angiotensin-converting enzyme by the lung. The product of this biochemical cascade, angiotensin 11, acts on specific receptors in multiple target organs. However, recent data demonstrate that renin and angiotensin are synthesized locally in many tissues (e.g., blood vessels, heart, lungs, kidneys, adrenals, and brain). The emerging concept is that angiotensin 11 produced locally at vascular tissue sites by an endogenous renin-angiotensin system may play an important role in the tonic contml of vascular resistance. This concept implies that local angiotensin II concentrations
VolullIe Hi:, ;-"-umber 6, Part I
Captopril in pregnant rat
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may exceed plasma levels and helps to explain why angiotensin-converting enzyme inhibitors lower vascular resistance in normal and low renin hypertension, why nephrectomized rats continue to produce angiotensin II, and why the duration of antihypertensive response to angiotensin-converting enzyme inhibitors far exceeds the duration of serum angiotensinconverting enzyme inhibition.' The results of this study show that chronic intraperitoneal captopril (-Hl mg/kg/day) lowered blood pressure by decreasing total peripheral resistance without affecting cardiac output. The decrease in total peripheral resistance was primarily a result of a significant decline in splanchnic and skin resistances, although small decrements in resistance occurred in many other organs including the kidney, adrenal, uterus, placenta, ovary, skeletal muscle, and brain. Because blood flow did not increase significantly in any organ, perfusion pressure must have fallen in parallel with resistance. These results differ from our previous studies of other antihypertensive drugs in the hypertensive, pregnant spontaneously hypertensive rat. Short-term administration of hydralazine and nifedipine produced
generalized vasodilatation except in the skin and in many of the splanchnic organs. ". II With labetalol the antihypertensive effect was primarily the result of a decline in cardiac output, but small decrements in resistance occurred in many regions except the carcass and splanchnic region. I I Although specific reasons for the different regional vascular effects are not precisely known, they are probably related to the different mechanisms of drug action and to distribution of receptors blocked by the various drugs. The fact that captopril had a more pronounced effect on skin and splanchnic organ resistance suggests that these vascular beds may be more dependent on the renin-angiotensin system for regulation of their tone than other vascular beds in the body. However, the other vascular beds may also be constricted by increased sympathetic nervous activity as a result of a baroreflex compensatory response to the decrease in blood pressure induced by dilatation in the skin and splanchnic beds. In our experience, the skin and splanchnic regions receive 20% to 30% of total cardiac output in the conscious, term-pregnant spontaneously hypertensive rat (unpublished data). Sizable falls in resistance in these large vascular beds could
1866
December 1990 Am J Obstet Gynccol
Mabie, Ahokas, and Sibai
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i Fig. 4. Cardiaclrenal and reproductive organ blood Hows and resistances at term in 10 control and 10 captopril-treated spontaneously hypertensive rats.
conceivably reduce blood pressure enough to trigger baroreflex compensatory vasoconstriction, thus offsetting generalized vasodilatation produced by captopril. Koike et a\. 15 administered captopril orally once daily at doses of 10 mg/kg and 30 mg/kg for 6 weeks to male spontaneously hypertensive rats. The decrease in systolic blood pressure was less than that observed in our study even at the 30 mg/kg dose. By use of the radioactive-labeled microsphere technique, cardiac output was found to increase in a dose-dependent manner and reached statistical significance in the highdose group, whereas total peripheral resistance decreased. Cerebral and renal blood flow increased dosedependently, whereas flow to other organs was not significantly affected. Antonaccio et a\. \(; reported that oral captopril (30 mg/kg) increased blood flow to all organs examined in spontaneously hypertensive rats, and the effect was statistically significant for the splanchnic area. We do not know why our results differ from these results, but it may be because of different routes of drug administration; because of constant, low-level exposure to captopril rather than bolus, high concentrations of the drug; or because we used pregnant female spontaneously hypertensive rats.
In this model use of captopril produced no adverse effect on uteroplacental blood flow. These findings are in contrast with the work of Ferris and Weir," who noted in normotensive pregnant rabbits that acute captopril administration (5 mg/kg intravenously) reduced uterine and placental blood flow. They speculated that blockade of angiotensin II synthesis with a resultant decrease in uterine prostaglandin E" synthesis may have been the cause. In chronic studies with rabbits, cap topril (2.5 or 5 mg subcutaneously daily) caused a marked decrease in fetal surviva\. Similarly, Broughton Pipkin et a\.'; found that administration of captopril (2.8 to 3.5 mg/kg intravenously) was associated with a much increased stillbirth rate in both sheep and rabbits; however, enalapril (1 or 2 mg/kg intravenously), which apparently does not cross the sheep placenta, was associated with a lower stillbirth rate. 17 The loss of four conceptuses in our captopril-treated group compared with only one conceptus in the control group, although not statistically significant, is at least consonant with the observations made in rabbits and sheep that use of captopril is associated with increased pregnancy wastage. The loss of conceptuses in both groups of rats apparently occurred early in gestation and was probably re-
Volume 163 Number 6, Part 1
lated to surgical manipulation of the uterus because there was no decaying tissue or other evidence of a second pregnancy found in any of the rats with a single fetus. Our previous experience" has been that manipulation of the uterus to adjust litter size occasionally causes one or more of the adjacent conceptuses to abort. The fact that the remaining pups were normal in weight and development supports this explanation. If captopril had induced uterine ischemia, the surviving fetus and placenta would be expected to be growth retarded. This does not conclusively rule out the possibility that captopril caused the abortions, and further study is needed in this area. In human pregnancy angiotensin-converting enzyme inhibitor therapy has been associated with several fetal and maternal complications including hypotension, growth retardation, oligohydramnios, anuria, renal failure, congenital malformations, stillbirth, and neonatal death."-10 However, more favorable results have been reported. Coen et al. 18 treated a patient with chronic glomerulonephritis throughout a twin pregnancy with a combination of captopril, hydralazine, and metoprolol. At term she was delivered of growthretarded twins whose subsequent course to 10 months of age was unremarkable. Mochizuki et al. 19 reported good results with captopril as part of combination therapy in late pregnancy in three patients. Kreft-Jais et al!" reported the results of a French survey of pregnancies exposed to angiotensin-converting enzyme inhibitors between June 1985 and December 1986. Twenty-two women received captopril and nine received enalapril. Most women had renal disease or chronic essential hypertension. Two stillbirths occurred in the captopril group and one in the enalapril group. Pre term delivery occurred in 11 women who were given captopril and in one given enalapril. Six of 26 live-born babies were growth retarded. In conclusion, chronic administration of captopril lowered blood pressure in the pregnant, hypertensive rat by decreasing total peripheral resistance without affecting cardiac output. Utero placental perfusion was unchanged, and no fetal growth retardation or congenital anomalies were noted. Nevertheless, because of conflicting animal data, potential risks to the fetus, and the availability of alternate drugs, the use of captopril in pregnant women should be avoided until further animal studies and human drug trials prove its safety. We thank Ed B. Cannon for his laboratory technical assistance. REFERENCES I. Bakris GL, Frolich ED. The evolution of antihypertensive therapy: an overview of four decades of experience. J Am Coll Cardiol 1989;14:1595-1608.
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2. Williams GH. Converting-enzyme inhibitors in the treatment of hypertension. N Engl J Med 1988;319: 1517-25. 3. Dzau VJ. Implications of local angiotensin production in cardiovascular physiology and pharmacology. Am J Cardiol 1987;57:59A-65A. 4. Brogden RN, Todd PA, Sorkin EM. Captopril: an update on its pharmacodynamic and pharmocokinetic properties, and therapeutic use in hypertension and congestive heart failure. Drugs 1988;36:540-600. 5. Ferris TF, Weir EK. Effect of captopril on uterine blood flow and prostaglandin E synthesis in the pregnant rabbit. J Clin Invest 1983;71 :809-15. 6. Broughton Pipkin F, Symonds EM, Turner SR. The effect of captopril (SQI4, 225) upon mother and fetus in the chronically cannulated ewe and in the pregnant rabbit. J PhysioI1982;323:415-22. 7. Duminy PC, Burger P du T. Fetal abnormality associated with the use of captopril during pregnancy. S Afr Med J 1981 ;60:805. 8. Broughton Pipkin F, Baker PN, Symonds EM. ACE inhibitors in pregnancy. Lancet 1989;2:96-7. 9. Guignard JP, Gouyon JB. Adverse effect of drugs on the immature kidney. Bioi Neonate 1988;53:243-52. 10. Lindheimer MD, Barron WM. Enalapril and pregnancyinduced hypertension. Ann Intern Med 1988; 108:911. II. Ahokas RA, Sibai BM. The relationship between experimentally determined litter size and maternal blood pressure in spontaneously hypertensive rats. AM J OBSTET GYNECOL 1990;162:841-7. 12. Lipshitz J, Ahokas RA, Reynolds SL. The effect of hydralazine on placental perfusion in the spontaneously hypertensive rat. AM J OBSTEl' GYNECOL 1987; 156:356-9. 13. Ahokas RA, Sibai BM, Mabie WC, Anderson GD. Nifedipine does not adversely affect uteroplacental blood flow in the hypertensive term-pregnant rat. AM J OBSTET GyNECOL 1988;159:1440-5. 14. Ahokas RA, Mabie WC, Sibai BM, Anderson GD. Labetalol does not decrease placental perfusion in the hypertensive term-pregnant rat. AM J OBSTET GYNECOL 1989; 160:480-4. 15. Koike H, Ito K, Miyamoto M, Nishino H. Effects of longterm blockade of angiotensin converting enzyme with captopril (SQ 14, 225) on hemodynamics and circulating blood volume in SHR. Hypertension 1980;2:299-303. 16. Antonaccio MJ, Rubin B, Horovitz ZP. Effects of captopril in animal models of hypertension. Clin Exp Hypertens 1980;2(3, 4):613-7. 17. Broughton Pipkin F, Wallace CF. The effect of enalapril (MK 421), an angiotensin converting enzyme inhibitor, on the conscious pregnant ewe and her fetus. Br J Pharmacol 1986;87:533-42. 18. Coen G, Cugini P, Gerlini G, Finistauri D, Cinotti A. Successful treatment of long-lasting severe hypertension with captopril during a twin pregnancy. Nephron 1985;40: 498-500. 19. Mochizuki M, Maruo T, Motoyama S. Treatment of hypertension in pregnancy by a combined drug regimen including captopril. Clin Exp Hypertens 1986;B5(l):6978. 20. Kreft-Jais C, Plouin PF, Tchobroutsky C, Boutroy MJ. Angiotensin-converting enzyme inhibitors during pregnancy: a survey of 22 patients given captopril and 9 given enalapril. Br J Obstet Gynaecol 1988;95:420-3.
Volume 163 Number 6, Part 1
8.
9. 10.
II. 12.
13.
14.
manifestation of pregnancy-induced hypertension. Circulation 1987;75:956. Goodman RP, Killam AP, Brash AR, Branch RA. Prostacyclin production during pregnancy: comparison of production during normal pregnancy and pregnancy complicated by hypertension. A~I j OBSTET GY:-iECOL 1982;142:817. Walsh SW. Preeclampsia: an imbalance in placental prostacyclin and thromboxane production. AM j OBSTET Gy:-iECOL 1985;152:335. Fitzgerald Dj, Mayo G, Catella F, Entmann S, Fitzgerald GA. Increased thromboxane biosynthesis in normal pregnancy is mainly derived from platelets. AM j OBSTET Gy:-;ECOL 1987;157:325. Beaufils M, Uzan S, Donsimoni R, Colau jC. Prevention of pre-eclampsia by early anti platelet therapy. Lancet 1985;1:840. Wallenburg H CS, Dekker GA, Makovitz jW, Rotmans P. Low-dose aspirin prevents pregnancy-induced hypertension and preeclampsia in angiotensin-sensitive primigravidae. Lancet 1986; 1: I. Schiff E, Peleg E, Goldenberg M, et al. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. N Engl j Med 1989;321 :351. Spitz B, Magness RR, Cox SM, Brown CEL, Rosenfeld CR, Gant NF. Low-dose aspirin. I. Effect on angiotensin II pressor responses and blood prostaglandin concentra-
15.
16.
17. 18. 19. 20. 21.
22.
tions in pregnant women sensitive to angiotensin II. AM j OBSTET GYNECOL 1988; 159: 1035. Sanchez-Ramos L, O'Sullivan M, Garrido-CalderonJ. Effect oflow-dose aspirin on angiotensin II pressor response in human pregnancy. AM j OBSTET GYNECOL 1987;156: 193. Caruso A, Ferrazzani S, DeCarolis S, Lanzone A, Mancuso S. Effects of low-dose aspirin on vascular sensitivity to angiotensin II and on 24 hours arterial blood pressure in pregnancy. Clin Exp Hypertens Hypertens Pregnancy 1988; B7:171. Cunningham FG, MacDonald PC, Gant NF. Hypertensive disorders in pregnancy. In: Williams' obstetrics. 18th ed. Norwalk, Connecticut: Appleton & Lange, 1989:653. Sibai BM, Mirro R, Chesney CM, Leffler C. Low-dose aspirin in pregnancy. Obstet Gynecol 1989;74:551. Friedman SA. Preeclampsia: a review of the role of prostaglandins. Obstet Gynecol 1988;71:122. Chesley LC. Hypertension in pregnancy: definitions, familial factor, and remote prognosis. Kidney Int 1980; 18 (suppl):234. Sutherland A, Cooper DW, Howie PW, Liston WA, MacGillivray I. The incidence of severe pre-eclampsia amongst mothers and mothers-in-law of pre-eclamptics and controls. Br j Obstet GynaecoI1981;88:785. Cooper DW, Liston WA. Genetic control of severe preeclampsia. j Med Genet 1979; 16:409.
Maternal and uteroplacental hemodynamic effects of chronic captopril in the hypertensive, term-pregnant rat William C. Mabie, MD, Robert A. Ahokas, PhD, and Baha M. Sibai, MD Memphis, Tennessee The chronic effects of captopril on maternal hemodynamics and organ perfusion were investigated in 10 untreated and 10 captopril-treated pregnant spontaneously hypertensive rats by means of the radioactive-labeled microsphere technique. The normal decrease in blood pressure during gestation was prevented by reduction of litter size to two conceptuses on day 7 of gestation. Captopril (=10 mg/kg/day) or drug vehicle (50% ethyl alcohol) was administered intraperitoneally by an osmotic pump from day 7 to 21. At term mean arterial pressure was 23% lower in the captopril-treated group as the result of a 29% decrease in total peripheral resistance without a significant change in cardiac output. The decrease in total peripheral resistance was primarily caused by a decline in splanchnic and skin resistances. Maternal organ and uteroplacental perfusion were not significantly altered. We conclude that administration of captopril during the last 2 weeks of pregnancy in the hypertensive rat effectively lowers maternal blood pressure without adverse effects on organ and uteroplacental perfusion. (AM J OSSlEl GVNECOL 1990;163:1861-7.)
Key words: Captopril, total peripheral resistance, placental perfusion, spontaneously hypertensive rat
Frorn the Division of Maternal-Fetal Medicine, Departrnent of Obstetrics and Gynecology, University of Tennessee-Mernphis. Presented at the Thirty-seventh Annual Meeting of the Society for Gynecologic [nvestigation, St. Louis, Missouri, March 21-24,1990. Reprint requests: Williarn C. Mabie, MD, Departrnent of Obstetrics and Gynecology, Universif.V of Tennessee-Mernphis, 853 jefferson Ave., Mernphis, TN 38103.
6/6/24774
In 1981 captopril was approved by the Food and Drug Administration for use as an antihypertensive agent in the United States. I Since then two other angiotensin-converting enzyme inhibitors, enalapril and lisinopril, have been approved and at least 14 other such inhibitors are under development. 2 Because of 1861
1862 Mabie, Ahokas, and Sibai
their efficacy and low side-effect profile angiotensinconverting enzyme inhibitors are widely used as firstline therapy for hypertension. The mechanism of action of the angiotensinconverting enzyme inhibitors is not completely understood, but it is thought that they induce vasodilatation by inhibiting angiotensin-converting enzyme, the enzyme that converts angiotensin I to angiotensin II. In addition to being a potent vasoconstrictor, angiotensin II stimulates aldosterone secretion and increases sympathetic outflow centrally. Because angiotensinconverting enzyme is identical to kininase II, which inactivates bradykinin, an additional antihypertensive effect may result from increased bradykinin levels. Finally, certain angiotensin-converting enzyme inhibitors increase synthesis of the vasodilating prostaglandins E2 and 12 • 2 •4 Accumulating evidence indicates that the major site of angiotensin II production is not in blood but in tissues (e.g., vascular, cardiac, renal, and brain). The decrease in blood pressure correlates better with the degree of inhibition of the vascular tissue reninangiotensin system than with the circulating reninangiotensin system. 2 As with any antihypertensive drug, the primary concerns about the use of captopril in pregnancy are the possible adverse effects on placental perfusion and the risk of congenital malformations. Captopril caused fetal death in rabbits, apparently by reduction of uteroplacental perfusion.' It caused maternal and fetal hypotension and stillbirth in sheep.6 Although results are conflicting, congenital malformations and other fetal complications have been associated with its use in human pregnancy.7-9 Therefore it has been recommended that captopril not be used during pregnancy.8. 10 The spontaneously hypertensive rat is widely accepted as a model of human essential hypertension. However, even in this genetically hypertensive animal, pregnancy has a profound blood pressure-lowering effect. During the last week of gestation blood pressure progressively decreases and usually reaches normotensive levels by term. We have recently shown that the magnitude of the decrease in blood pressure in the pregnant spontaneously hypertensive rat is directly proportional to litter size." The resistances of virtually all the maternal organ vascular beds, including the uterus and placentas, at term are inversely related to litter size. Thus reducing litter size to one or two conceptuses shortly after implantation prevents the normal decrease in blood pressure, producing a model of essential hypertension during pregnancy. The purpose of this study was to evaluate the effects oflowering maternal blood pressure with captopril during the last 2 weeks of pregnancy on maternal and utero placental hemodynamics at term in the hypertensive, pregnant rat.
December 1990 Am J Obstet Gynecol
Material and methods
This research conforms with the "Guiding Principles in the Care and Use of Laboratory Animals" approved by the Council of the American Physiological Society and with federal laws and regulations. The protocol used was approved by the University of Tennessee, Memphis, Animal Care and Use Committee. Virgin female spontaneously hypertensive rats (10 to 12 weeks of age) were purchased from Harlan/Sprague-Dawley, Inc. (Indianapolis). They were housed four per cage in a temperature-controlled room (23 0 ± 10 C) with lights on from 7 AM to 7 PM and were fed Purina Laboratory Rodent Chow (Ralston Purina, St. Louis) as desired with tap water to drink. For breeding, the females were housed 1 : 1 with mature male spontaneously hypertensive rats. Vaginal smears were checked daily in the morning for the presence of spermatozoa. The day vaginal smears were sperm positive was designated day 0 of pregnancy and the timed pregnant rats were housed singly throughout pregnancy. Systolic blood pressure was measured by tail-cuff plethysmography (IITC, Inc., Woodland Hills, Calif.) and was monitored every other day throughout gestation. For these measurements the rats were prewarmed to 300 C for 15 to 20 minutes in an incubator. They were then placed in a Plexiglas restraining cage and an inflatable cuff with a photoelectric sensor was placed around the base of the tail. The cuff was then inflated to a pressure of 250 mm Hg. The pressure was gradually released until a pulse was detected (systolic blood pressure). The mean of 3 to 5 determinations was recorded for each day. On day 7 of gestation a laparotomy was performed with the rat under light methoxyflurane anesthesia and litter size was reduced to two (one in each uterine horn) by aspiration of embryos through small incisions in the anti mesometrial uterine wall. The uterine incisions were then closed with sutures. A sterile osmotic minipump (model 2001, Alza Corp., Palo Alto, Calif.) filled with either a sterile solution of captopril (200 mg/ml) or drug vehicle (50% ethyl alcohol) was placed in the abdominal cavity to administer the contents intra peritoneally. Infusion rate was 0.5 f,Ll/hr (2.4 mg of captopril per day). This rate of infusion resulted in a dosage of -10 to 12 mg/kg/day. The abdominal incisions were closed, and the rats were injected with penicillin G (30,000 U /kg intramuscularly) and returned to their cages for the duration of pregnancy. On postmating day 21 (the day before delivery), mean arterial pressure, cardiac output, and organ blood flows were measured with the radioactive-labeled microsphere technique described previously.12-14 Mean arterial pressure, cardiac output, and organ blood flows
Captopril in pregnant rat
VoluI1Ie Hi:l ""I1Iber (i. Pan 1
1863
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were measured after a minimum 2-hour anesthesia recovery period. The data were expressed as the mean ± SEM. Systolic blood pressure data was analyzed by two-way analysis of variance. Student t test was used for comparison of mean arterial pressure, cardiac output, total peripheral resistance, organ flows, and organ vascular resistances between groups. The 95% confidence level was accepted as statistically significant for all analyses. Results
Fig. I depicts the mean systolic blood pressure measured on alternate days during gestation for the untreated and captopril-treated rats. On day 0, mean systolic blood pressure in the two groups was not different. On day 7, the day treatment was started, mean systolic blood pressure was 186 ± 3 mm Hg and 185 ± 4 mm Hg in the untreated and captopril-treated groups, respectively. Captopril produced a significant reduction in mean systolic blood pressure that persisted throughout gestation beginning on the first day or two after pump implantation. On day 21, mean systolic blood pressure was 186 ± 6 mm Hg and 143 ± 2 mm Hg in the untreated and captopril-treated rats, respectively. Table I shows the total body, maternal organ, and fetal and placental weights of the untreated and
captopril-treated rats. Net maternal weight, but not mean fetal or placental weight, was significantly lower in the captopril-treated compared with the untreated rats. This was primarily a result of lower carcass, skin, and liver weights. Captopril treatment may have resulted in reduced food consumption, although this factor was not measured. Nine of the control rats had two fetuses at term compared with six of the captopriltreated rats, a nonsignificant difference. One rat in the control group and four in the captopril-treated group aborted one conceptus and carried one to term. There was no decaying tissue found in the uteri of the rats with only one fetus that would suggest recent fetal death, and all living fetuses appeared structurally normal. There was no significant difference in mean fetal or placental weight between the two groups. The effects of captopril on maternal hemodynamics at term are summarized in Fig. 2. Mean arterial pressure was 23% lower in the captopril-treated group than in the control group (130.2 ± 4.7 mm Hg vs 169.0 ± 3.6 mm Hg, p < 0.01). Maternal cardiac index was unchanged but total peripheral resistance of the captopril-treated rats was 29% lower than that of the untreated rats (4.68 ± 0.38 vs 3.33 ± 0.30 mm Hg/mllminl 100/gm, p < 0.02). There was a nearly significant increase (p = 0.(6) in apparent lung blood flow (1.6 ± 0.3% vs 5.2 ± 1.8%
1864
Mabie, Ahokas, and Sibai
December 1990 Am.J Obstet Gvnecol
Mean Arterial Pressure 2~~------------------~
Cardiac Index
Total Peripheral Resistance
f Control
Captoprll
Control
Captoprll
Captopril
Fig. 2. Mean arterial pressure, cardiac index, and total peripheral resistance at term in 10 control and 10 captopril-treated (= 10 mg/kg/day) spontaneously hypertensive rats.
Table I. Total body, maternal organ, and fetal and placental weights of untreated and captopril-treated rats COlltrol
Total body weight, day 0 (gm) Total body weight, day 21 (gm) Net maternal weight, day 21 (gm) Carcass (gm) Skin (gm) Brain (gm) Heart (gm) Lungs (gm) Stomach (gm) Small intestine (gm) Large intestine (gm) Liver (gm) Spleen (gm) Pancreas (gm) Kidneys (gm) Adrenal glands (gm) Ovaries (gm) Uterus (gIll) Litter size Mean fetal weight (gm) Mean placental weight (gm)
Cal)topril
197.2 ± 3.5 251.2 ± 7.0 207.8 ± 6.0 142.33 ± 4.74 34.45 ± 0.92 1.82 ± 0.03 1.06 ± 0.04 1.21 ± 0.04 1.30 ± 0.05 4.95±0.18 :1.32 ± 0.11 11.07 ± O.:H 0.45 ± 0.18 0.67 ± 0.07 1.56 ± 0.17 0.08 ± 0.01 0.11 ± OJ)I 2.1:') ± 0.12 19/20
4.72 ± 0.22 0.58 ± 0.03
of cardiac output) in the untreated and captopriltreated groups, respectively. This may have been a result of the opening of systemic arteriovenous shunts by captopril. Fig. 3 illustrates the splanchnic, skin, and remaining carcass blood flows and vascular resistances of untreated and captopril-treated rats. Captopril produced significant reductions in splanchnic and skin vascular resistances but had no significant affect on splanchnic, skin, or carcass blood flows. Fig. 4 summarizes the cardiac, renal, adrenal, and reproductive organ blood flows and resistances in untreated and captopril-treated rats. There were no statistically significant differences between groups in either blood flow or resistance values.
211.0 263.6 189.6 129.63 32.09 1.80 0.9:) 1.17 1.25 4.81 3.21 10.1:) 0.48 0.62 1.53 0.08 0.11 1.71
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
7.0 5.0 :1.5 2.49 0.72 0.03 0.06 0.03 0.03 0.19 0.11 0.28 0.03 0.05 0.05 0.01 0.01 0.11
](,/20
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4.6:") ± 0.26 0.59 ± 0.09
Comment
The traditional concept of the renin-angiotensin system is that of a circulation-borne endocrine system in which angiotensinogen is produced by the liver, renin by the kidney, and angiotensin-converting enzyme by the lung. The product of this biochemical cascade, angiotensin 11, acts on specific receptors in multiple target organs. However, recent data demonstrate that renin and angiotensin are synthesized locally in many tissues (e.g., blood vessels, heart, lungs, kidneys, adrenals, and brain). The emerging concept is that angiotensin 11 produced locally at vascular tissue sites by an endogenous renin-angiotensin system may play an important role in the tonic contml of vascular resistance. This concept implies that local angiotensin II concentrations
VolullIe Hi:, ;-"-umber 6, Part I
Captopril in pregnant rat
Splanchnic 2000
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1865
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may exceed plasma levels and helps to explain why angiotensin-converting enzyme inhibitors lower vascular resistance in normal and low renin hypertension, why nephrectomized rats continue to produce angiotensin II, and why the duration of antihypertensive response to angiotensin-converting enzyme inhibitors far exceeds the duration of serum angiotensinconverting enzyme inhibition.' The results of this study show that chronic intraperitoneal captopril (-Hl mg/kg/day) lowered blood pressure by decreasing total peripheral resistance without affecting cardiac output. The decrease in total peripheral resistance was primarily a result of a significant decline in splanchnic and skin resistances, although small decrements in resistance occurred in many other organs including the kidney, adrenal, uterus, placenta, ovary, skeletal muscle, and brain. Because blood flow did not increase significantly in any organ, perfusion pressure must have fallen in parallel with resistance. These results differ from our previous studies of other antihypertensive drugs in the hypertensive, pregnant spontaneously hypertensive rat. Short-term administration of hydralazine and nifedipine produced
generalized vasodilatation except in the skin and in many of the splanchnic organs. ". II With labetalol the antihypertensive effect was primarily the result of a decline in cardiac output, but small decrements in resistance occurred in many regions except the carcass and splanchnic region. I I Although specific reasons for the different regional vascular effects are not precisely known, they are probably related to the different mechanisms of drug action and to distribution of receptors blocked by the various drugs. The fact that captopril had a more pronounced effect on skin and splanchnic organ resistance suggests that these vascular beds may be more dependent on the renin-angiotensin system for regulation of their tone than other vascular beds in the body. However, the other vascular beds may also be constricted by increased sympathetic nervous activity as a result of a baroreflex compensatory response to the decrease in blood pressure induced by dilatation in the skin and splanchnic beds. In our experience, the skin and splanchnic regions receive 20% to 30% of total cardiac output in the conscious, term-pregnant spontaneously hypertensive rat (unpublished data). Sizable falls in resistance in these large vascular beds could
1866
December 1990 Am J Obstet Gynccol
Mabie, Ahokas, and Sibai
Cardiac/Renal
Flow
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i Fig. 4. Cardiaclrenal and reproductive organ blood Hows and resistances at term in 10 control and 10 captopril-treated spontaneously hypertensive rats.
conceivably reduce blood pressure enough to trigger baroreflex compensatory vasoconstriction, thus offsetting generalized vasodilatation produced by captopril. Koike et a\. 15 administered captopril orally once daily at doses of 10 mg/kg and 30 mg/kg for 6 weeks to male spontaneously hypertensive rats. The decrease in systolic blood pressure was less than that observed in our study even at the 30 mg/kg dose. By use of the radioactive-labeled microsphere technique, cardiac output was found to increase in a dose-dependent manner and reached statistical significance in the highdose group, whereas total peripheral resistance decreased. Cerebral and renal blood flow increased dosedependently, whereas flow to other organs was not significantly affected. Antonaccio et a\. \(; reported that oral captopril (30 mg/kg) increased blood flow to all organs examined in spontaneously hypertensive rats, and the effect was statistically significant for the splanchnic area. We do not know why our results differ from these results, but it may be because of different routes of drug administration; because of constant, low-level exposure to captopril rather than bolus, high concentrations of the drug; or because we used pregnant female spontaneously hypertensive rats.
In this model use of captopril produced no adverse effect on uteroplacental blood flow. These findings are in contrast with the work of Ferris and Weir," who noted in normotensive pregnant rabbits that acute captopril administration (5 mg/kg intravenously) reduced uterine and placental blood flow. They speculated that blockade of angiotensin II synthesis with a resultant decrease in uterine prostaglandin E" synthesis may have been the cause. In chronic studies with rabbits, cap topril (2.5 or 5 mg subcutaneously daily) caused a marked decrease in fetal surviva\. Similarly, Broughton Pipkin et a\.'; found that administration of captopril (2.8 to 3.5 mg/kg intravenously) was associated with a much increased stillbirth rate in both sheep and rabbits; however, enalapril (1 or 2 mg/kg intravenously), which apparently does not cross the sheep placenta, was associated with a lower stillbirth rate. 17 The loss of four conceptuses in our captopril-treated group compared with only one conceptus in the control group, although not statistically significant, is at least consonant with the observations made in rabbits and sheep that use of captopril is associated with increased pregnancy wastage. The loss of conceptuses in both groups of rats apparently occurred early in gestation and was probably re-
Volume 163 Number 6, Part 1
lated to surgical manipulation of the uterus because there was no decaying tissue or other evidence of a second pregnancy found in any of the rats with a single fetus. Our previous experience" has been that manipulation of the uterus to adjust litter size occasionally causes one or more of the adjacent conceptuses to abort. The fact that the remaining pups were normal in weight and development supports this explanation. If captopril had induced uterine ischemia, the surviving fetus and placenta would be expected to be growth retarded. This does not conclusively rule out the possibility that captopril caused the abortions, and further study is needed in this area. In human pregnancy angiotensin-converting enzyme inhibitor therapy has been associated with several fetal and maternal complications including hypotension, growth retardation, oligohydramnios, anuria, renal failure, congenital malformations, stillbirth, and neonatal death."-10 However, more favorable results have been reported. Coen et al. 18 treated a patient with chronic glomerulonephritis throughout a twin pregnancy with a combination of captopril, hydralazine, and metoprolol. At term she was delivered of growthretarded twins whose subsequent course to 10 months of age was unremarkable. Mochizuki et al. 19 reported good results with captopril as part of combination therapy in late pregnancy in three patients. Kreft-Jais et al!" reported the results of a French survey of pregnancies exposed to angiotensin-converting enzyme inhibitors between June 1985 and December 1986. Twenty-two women received captopril and nine received enalapril. Most women had renal disease or chronic essential hypertension. Two stillbirths occurred in the captopril group and one in the enalapril group. Pre term delivery occurred in 11 women who were given captopril and in one given enalapril. Six of 26 live-born babies were growth retarded. In conclusion, chronic administration of captopril lowered blood pressure in the pregnant, hypertensive rat by decreasing total peripheral resistance without affecting cardiac output. Utero placental perfusion was unchanged, and no fetal growth retardation or congenital anomalies were noted. Nevertheless, because of conflicting animal data, potential risks to the fetus, and the availability of alternate drugs, the use of captopril in pregnant women should be avoided until further animal studies and human drug trials prove its safety. We thank Ed B. Cannon for his laboratory technical assistance. REFERENCES I. Bakris GL, Frolich ED. The evolution of antihypertensive therapy: an overview of four decades of experience. J Am Coll Cardiol 1989;14:1595-1608.
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2. Williams GH. Converting-enzyme inhibitors in the treatment of hypertension. N Engl J Med 1988;319: 1517-25. 3. Dzau VJ. Implications of local angiotensin production in cardiovascular physiology and pharmacology. Am J Cardiol 1987;57:59A-65A. 4. Brogden RN, Todd PA, Sorkin EM. Captopril: an update on its pharmacodynamic and pharmocokinetic properties, and therapeutic use in hypertension and congestive heart failure. Drugs 1988;36:540-600. 5. Ferris TF, Weir EK. Effect of captopril on uterine blood flow and prostaglandin E synthesis in the pregnant rabbit. J Clin Invest 1983;71 :809-15. 6. Broughton Pipkin F, Symonds EM, Turner SR. The effect of captopril (SQI4, 225) upon mother and fetus in the chronically cannulated ewe and in the pregnant rabbit. J PhysioI1982;323:415-22. 7. Duminy PC, Burger P du T. Fetal abnormality associated with the use of captopril during pregnancy. S Afr Med J 1981 ;60:805. 8. Broughton Pipkin F, Baker PN, Symonds EM. ACE inhibitors in pregnancy. Lancet 1989;2:96-7. 9. Guignard JP, Gouyon JB. Adverse effect of drugs on the immature kidney. Bioi Neonate 1988;53:243-52. 10. Lindheimer MD, Barron WM. Enalapril and pregnancyinduced hypertension. Ann Intern Med 1988; 108:911. II. Ahokas RA, Sibai BM. The relationship between experimentally determined litter size and maternal blood pressure in spontaneously hypertensive rats. AM J OBSTET GYNECOL 1990;162:841-7. 12. Lipshitz J, Ahokas RA, Reynolds SL. The effect of hydralazine on placental perfusion in the spontaneously hypertensive rat. AM J OBSTEl' GYNECOL 1987; 156:356-9. 13. Ahokas RA, Sibai BM, Mabie WC, Anderson GD. Nifedipine does not adversely affect uteroplacental blood flow in the hypertensive term-pregnant rat. AM J OBSTET GyNECOL 1988;159:1440-5. 14. Ahokas RA, Mabie WC, Sibai BM, Anderson GD. Labetalol does not decrease placental perfusion in the hypertensive term-pregnant rat. AM J OBSTET GYNECOL 1989; 160:480-4. 15. Koike H, Ito K, Miyamoto M, Nishino H. Effects of longterm blockade of angiotensin converting enzyme with captopril (SQ 14, 225) on hemodynamics and circulating blood volume in SHR. Hypertension 1980;2:299-303. 16. Antonaccio MJ, Rubin B, Horovitz ZP. Effects of captopril in animal models of hypertension. Clin Exp Hypertens 1980;2(3, 4):613-7. 17. Broughton Pipkin F, Wallace CF. The effect of enalapril (MK 421), an angiotensin converting enzyme inhibitor, on the conscious pregnant ewe and her fetus. Br J Pharmacol 1986;87:533-42. 18. Coen G, Cugini P, Gerlini G, Finistauri D, Cinotti A. Successful treatment of long-lasting severe hypertension with captopril during a twin pregnancy. Nephron 1985;40: 498-500. 19. Mochizuki M, Maruo T, Motoyama S. Treatment of hypertension in pregnancy by a combined drug regimen including captopril. Clin Exp Hypertens 1986;B5(l):6978. 20. Kreft-Jais C, Plouin PF, Tchobroutsky C, Boutroy MJ. Angiotensin-converting enzyme inhibitors during pregnancy: a survey of 22 patients given captopril and 9 given enalapril. Br J Obstet Gynaecol 1988;95:420-3.