The role of self-rated health in the association between chronic somatic diseases and climacteric-related symptoms.

OBJECTIVES: We have previously shown an association between several chronic somatic diseases and climacteric-related symptoms. This time, we investigated whether self-rated health (SRH) contributes to this association. METHODS: The Women's Health Questionnaire was used to evaluate the climacteric-related symptoms, and existence of the diseases was investigated in 3421 women (41-54 years). In our previous study, the associations were defined with multivariable analyses. In the present study, SRH (good, moderate or bad) was included as a covariate. RESULTS: Most of the previously found associations between the diseases and the symptoms lost their significance. Accordingly, SRH played an important role in the association between the diseases and the symptoms related to the climacteric. CONCLUSIONS: SRH seems to be of significant importance regarding the relationship between the chronic somatic diseases and the symptoms related to climacteric. Most of the diseases are not associated with the climacteric-related symptoms if the disease does not deteriorate the SRH. Thus, women's own perception of their health is crucial for their symptomatology.

Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) are drugs that exhibit both estrogen agonistic and antagonistic effects that are tissue-specific. Ospemifene (FC-1271a) is a novel SERM compound, which has been shown in animal models to have estrogen-like effects on bone and the cardiovascular system, while having antiestrogen-like effects in uterus and breast. In this study, we investigated the effects of ospemifene on the uterine endometrium, vaginal maturation index and hormonal status in healthy postmenopausal women. METHODS: The study was conducted as a double-blind, placebo-controlled phase I study, where 40 healthy postmenopausal women volunteers were randomized to receive daily oral doses of ospemifene either 25, 50, 100 or 200 mg or placebo for 12 weeks. Vaginal ultrasonography and endometrial biopsy were performed and vaginal maturation index determined at baseline and at 12 weeks' visit. Serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone (FSH), sex-hormone binding globulin (SHBG), parathyroid hormone and prolactin were determined from samples taken at baseline, at 4 days and at 4, 12, and 16 weeks' visits. Climacteric symptoms were assessed using 12 visual analogue scales (VAS) at baseline and at the end of the study. RESULTS: No clinically significant changes were seen in endometrial thickness at any dose level. Ospemifene exerted a very weak estrogenic effect on endometrial histology. On the other hand, it induced a clear estrogenic effect on vaginal epithelium. Among the endocrine parameters only FSH and SHBG showed significant dose dependent changes; FSH decreased and SHBG increased during the treatment. In general, ospemifene was well tolerated. The 25 and 50 mg doses tended to reduce climacteric symptoms, but no statistically significant differences were observed between different doses of ospemifene and placebo. The highest dose level (200 mg) induced more subjective adverse reactions, especially hot flushes, than lower doses. CONCLUSION: Our study suggests that a safe and well tolerated dose of ospemifene for potential clinical use may be between 25 and 100 mg. Further studies are needed to substantiate the results of this Phase I pilot study.

Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator.

PURPOSE: New selective estrogen-receptor modulators for the treatment and prevention of osteoporosis, cardiovascular disease and breast cancer are currently the focus of intense research. (Deaminohydroxy)toremifene (Z-2-[4-(4-chloro- 1,2-diphenyl-but-1-enyl)phenoxy]ethanol; FC-1271a) has been shown to prevent bone resorption in rats while having no or weak estrogen-like effects on the uterus, which makes it a good candidate drug for osteoporosis prevention. Our purpose here was to examine the pharmacokinetics of (deaminohydroxy)toremifene in humans included in two phase-I studies. METHODS: The first was a single-dose, dose-escalation study with 28 healthy male volunteers. Doses ranged from 10 mg to 800 mg. The second study was conducted during a 12-week period with 40 healthy, post-menopausal women, who received repeated oral doses of 25-200 mg. Standard pharmacokinetic parameters were assessed. RESULTS: In the single-dose study, time to reach peak concentration (tmax) ranged from 1.3 h to 4.0 h; peak concentration (Cmax) ranged from 15 ng/ml to 445 ng/ ml; and the estimated terminal elimination half-life (mean +/- SD; t1/2) was 24.8 +/- 7.0 h. In the repeated-dose study, tmax ranged from 1.9 h to 2.6 h at 6 weeks and from 2.5 h to 2.9 h at 12 weeks. Cmax ranged from 295 ng/ml to 1,043 ng/ml at 6 weeks and from 25 ng/ml to 1211 ng/ml at 12 weeks. The average t1/2 at all dose levels was 29.7 +/- 1.5 h (overall mean +/- SD). Strong linear correlations between the dose and Cmax and between the dose and the area under the curve were observed in both studies. CONCLUSION: Our results indicate that (deaminohydroxy)toremifene has pharmacokinetics suitable for single daily dosing. The prophylactic use of this agent in women susceptible to development of osteoporosis, cardiovascular disease and breast cancer could, therefore, be tested using a once-daily dosing schedule similar to those of other hormone-replacement therapy regimens.

Effects of tocolytic treatment with ritodrine on cardiovascular autonomic regulation.

OBJECTIVE: To study the acute effects of tocolytic treatment with intravenous ritodrine on cardiovascular autonomic regulation. DESIGN: Validated methods to assess cardiovascular autonomic nervous function-heart rate and blood pressure variability and vagal cardiac baroreflex sensitivity-were measured before and during ritodrine infusion. SETTING: Turku University Central Hospital, Turku, Finland. SAMPLE: Twelve pregnant women admitted to hospital for threatened preterm labour. METHODS: Electrocardiogram and continuous noninvasive finger blood pressure signals were recorded in each woman, resting in a supine position. Autoregressive spectrum analysis was used to quantify short term heart rate and blood pressure variability. Vagal cardiac baroreflex sensitivity was measured as the bradycardia response to an intravenous bolus injection of phenylephrine. MAIN OUTCOME MEASURES: Vagal cardiac baroreflex sensitivity and spectrum analysis indices of short term heart rate and blood pressure variability. RESULTS: Ritodrine significantly decreased vagal cardiac baroreflex sensitivity as well as total (0.00-0.40 Hz), low frequency (0.04-0.15 Hz) and high frequency (0.15-0.40 Hz) power bands of the heart rate variability spectrum. Ritodrine significantly increased mean heart rate and the low frequency power band of the systolic blood pressure variability spectrum. CONCLUSIONS: In pregnant women with threatened preterm labour intravenous administration of ritodrine decreases vagal cardiac baroreflex sensitivity and vagal modulation of heart rate, and increases sympathetically mediated blood pressure variability. Decreased baroreflex sensitivity and heart rate variability are known to be associated with a poor prognosis in some patient groups, so the effects of ritodrine tocolysis may be unfavourable in women with impaired circulatory homeostasis.

Frequency of anal sphincter rupture at delivery in Sweden and Finland--result of difference in manual help to the baby's head.

BACKGROUND: Anal sphincter rupture is a serious complication of vaginal delivery and almost half the affected women have persistent defecatory symptoms despite adequate primary repair. During the past decade, the incidence of anal sphincter ruptures has been increasing in Sweden and is currently estimated to occur in 2.5% of vaginal deliveries. The aim of the study was to report the frequency of anal sphincter ruptures in two university hospitals in two Scandinavian countries, Malmö in Sweden and Turku in Finland, and analyze the potential determinants. METHODS: Retrospective analysis of a population of 30,933 deliveries (26,541 vaginal) during the years 1990 to 1994. RESULTS: The incidence of anal sphincter ruptures in Malmö, Sweden was 2.69%, and in Turku, Finland 0.36%. There were no significant population differences for the known risk factors (fetal weight, nulliparity or fetal head circumference). However, there is a difference in manual support given to the perineum and to the baby's head when crowning through the vaginal introitus between Malmö and Turku. The proportion of operative vaginal deliveries and abnormal presentations was significantly higher in Turku reflected in the lower Apgar score at 5 minutes and longer duration of second phase of labor. When high risk deliveries (operative vaginal delivery, abnormal presentation and newborns over 4,000 g) were excluded, the risk for anal sphincter ruptures was estimated to be 13 times higher in Malmö than in Turku. CONCLUSIONS: The difference in the incidence of anal sphincter rupture between Malmö, Sweden and Turku, Finland may be due to the difference in manual control of the baby's head when crowning.

Valsalva manoeuvre can be used to study baroreflex sensitivity in pregnancy.

OBJECTIVE: The aim of this study was to assess whether baroreflex sensitivity can be measured in a non-invasive manner with the Valsalva manoeuvre in pregnancy. STUDY DESIGN: Baroreflex sensitivity was measured from the reflex response to phenylephrine injection and phase four of the Valsalva manoeuvre in nine pregnant women at 27 (range 24-33) gestational weeks. RESULTS: Both the phenylephrine test and the Valsalva manoeuvre yielded similar estimates of baroreflex sensitivity (9.3 (4.1) ms/mmHg vs. 8.0 (5.2) ms/mmHg, Pearson's correlation coefficient r = 0.81, P < 0.008, linear regression BRSValsalva (ms/mmHg) = 1.03 x BRSPhenylephrine + 1.59). Comparable changes in heart rate and blood pressure were obtained with the phenylephrine test and the Valsalva manoeuvre. CONCLUSION: The physiological challenge caused by the Valsalva manoeuvre can be used to measure baroreflex sensitivity in pregnancy. A possibility to study baroreflex function non-invasively, without pharmacological intervention, benefits future research of blood pressure regulation in pregnancy.

Nitrous oxide inhalation: effects on maternal and fetal circulations at term.

OBJECTIVE: To evaluate the hemodynamic effects of nitrous oxide inhalation in normal term pregnancy. METHODS: Twenty healthy term pregnant women were given 30% nitrous oxide in pure oxygen for 2 minutes, and the hemodynamics were assessed by pulsed-wave color Doppler velocimetry of the uterine and internal carotid artery of the mother and the umbilical and middle cerebral artery of the fetus. Each vessel was assessed separately, allowing a 5-minute wash-out period between the inhalations. The measurements were continued for 2 minutes after the inhalation, and the pulsatility index (PI) was determined at 1-minute intervals. The maternal heart rate and blood pressure (BP) were recorded before and after inhalation; fetal well-being was confirmed with cardiotocography. Analysis of variance for repeated measurements and paired-sample t test were used for statistical analysis. RESULTS: A significant decrease in the PI of the maternal internal carotid artery was observed after 2-minutes of inhalation (from 0.83 +/- 0.22 to 0.71 +/- 0.20; P < .001). The uterine artery PI and maternal BP and heart rate were not affected by nitrous oxide. A significant decrease was evident even in the fetal middle cerebral artery PI (from 1.37 +/- 0.27 to 1.22 +/- 0.17; P = .02). The umbilical artery PI remained unchanged. CONCLUSION: Both maternal and fetal central vascular resistance were decreased by 30% nitrous oxide inhalation. So far, no adverse effects to mother or fetus have been demonstrated in clinical practice. However, preterm fetuses are susceptible to intracranial hemorrhage, and the cerebral hyperemia by nitrous oxide might increase the risk of hemorrhage in these fetuses. This hypothesis requires further investigation.

Autonomic cardiovascular control in pregnancy.

Pregnancy is associated with profound adaptive changes in the maternal hemodynamics. Although the autonomic nervous system plays a central role in the adaptation of the cardiovascular system to various needs, its role in the adaptation of the circulation to the demands of pregnancy is poorly understood. This paper reviews the literature of autonomic cardiovascular control in pregnancy as studied with the cardiovascular reflex tests. A Medline search and manual cross-referencing for prior publications were used. All papers found on the hemodynamic effects of the Valsalva maneuver, the orthostatic test, the deep breathing test, the isometric handgrip test and maternal heart rate variability in pregnancy were reviewed and all publications that studied short-term changes in maternal heart rate and blood pressure were included. The beginning of pregnancy is associated with sympathetic reactivity, whereas the latter half of pregnancy is characterized by increased hemodynamic stability during orthostatic stress. The heart rate response to the Valsalva maneuver is blunted in mid-pregnancy, possibly due to changes in the baroreflex and increased maternal blood volume. Heart rate variability is significantly reduced in the second trimester. Cardiovascular reflex tests can be used to study drug effects on maternal circulation non-invasively.

The hemodynamic effects of maternal hypo- and hyperoxygenation in healthy term pregnancies.

OBJECTIVE: To evaluate the hemodynamic effects of maternal hypo- and hyperoxygenation in normal term pregnancy. METHODS: Ten healthy women between 35-41 weeks' gestation were exposed to 10% oxygen in inspired air for 10 minutes and, after a 5-minute recovery period, to a stepwise increase in oxygenation with 50 and 100% oxygen for 10 minutes. Maternal ventilation, hemodynamics, and oxygenation were assessed noninvasively, and maternal and fetal vascular responses were assessed with pulsed-wave color Doppler velocimetry. Computerized cardiotocography was used for fetal heart rate (FHR) analysis. RESULTS: Substantial maternal hypoxia was achieved and accompanied by a statistically significant rise in the maternal heart rate (from 89 +/- 11 to 104 +/- 16 beats per minute) and systolic blood pressure (from 123 +/- 13 to 131 +/- 13 mmHg). Doppler measurements demonstrated a statistically significant decline in the pulsatility index (PI) of the maternal internal carotid artery (from 1.8 +/- 0.3 to 1.5 +/- 0.4) and an increase in the uterine artery PI (from 0.60 +/- 0.12 to 0.72 +/- 0.13). Baseline FHR, heart rate variability, and Doppler velocimetry in the umbilical artery and the middle cerebral artery showed no statistically significant changes. Hyperoxia did not cause changes in the maternal circulation, but the FHR decreased significantly (from 142 +/- 12 to 133 +/- 11 beats per minute). CONCLUSION: Acute short-term hypoxia modifies the maternal circulation, suggesting redistribution of maternal blood flow, but exerts no detectable effects on the healthy fetus. Maternal hyperoxygenation induces no apparent adverse effects.

Does thermal stress decrease uterine blood flow in hypertensive pregnancies?

The aim of the study was to determine the acute effects of thermal stress on maternal and fetal circulatory responses in normal and hypertensive patients. Therefore we studied 14 healthy pregnant women and 12 women with compromised pregnancies during short-term heat stress using color Doppler ultrasound in addition to conventional follow-up methods. The uterine vascular resistance increased significantly during the exposure in the high-risk pregnancy group without change in the control group. The results of the present study give strong support to our earlier studies that short-term heat stress seems to be safe in uncomplicated pregnancies but may be detrimental in high-risk pregnancies.

Vaginal and intracervical prostaglandin E2 for cervical ripening: a Doppler study of hemodynamic effects.

The hemodynamic effects of vaginally and intracervically administered prostaglandin E2 gel were evaluated by pulsed wave color Doppler ultrasound. Twenty term pregnant mothers were recruited. Mothers were randomized to receive either vaginal or intracervical prostaglandin E2 gel. The hemodynamics was assessed by repeated color Doppler velocimetry of the uterine artery and fetal umbilical and middle cerebral arteries; analysis of variance was used to test statistical significance. In the uterine artery a statistically significant rise (P < or = 0.001) of the pulsatility index (PI) was observed. A slightly higher rise of the PI was observed after intracervical administration, but the difference between the groups was not statistically significant (P = 0.4). The fetal PI remained unchanged both in the umbilical and cerebral vessels throughout the study. The rise in the uterine artery PI is probably caused by an increase in the uterine tone as prostaglandins of the E series usually cause vasodilation. No detectable fetal effects were evident.

Autonomic cardiovascular reflexes in pregnancy. A longitudinal study.

Cardiovascular reflexes were studied in 22 healthy women before they were pregnant, once during each pregnancy trimester and after delivery to evaluate the effect of pregnancy on autonomic control of haemodynamics. The Valsalva manoeuvre, the deep breathing test, the orthostatic test and the isometric handgrip test were used to assess changes in autonomic nervous function. We found that pregnancy altered the heart rate response in the Valsalva manoeuvre, the deep breathing test and the orthostatic tests. The deep breathing difference (p = 0.03) and max/min ratio (p = 0.03) decreased in pregnancy, whereas standing heart rate increased (p < 0.0001). Both the systolic and diastolic blood pressure increased after standing up during pregnancy. The circulatory responses to isometric exercise were not affected by pregnancy. The results show that parasympathetic responsiveness is decreased in pregnancy and that it returns to normal after delivery.

Use of medication during pregnancy--a prospective cohort study on use and policy of prescribing.

Pregnancy is associated with special problems with respect in selection of medication and dosage, primarily due to potential teratogenic or toxic effects on the fetus by the drug itself, and secondly due to the physiologic adjustments in the mother in response to pregnancy. This prospective survey was designed to record the use of medications and the policy of prescribing during the course of pregnancy. In total, 5851 pregnant women residing in a county in southwestern Finland during the period June 15, 1987 and June 14, 1988 were studied, which is 69% of the total amount of births in the same area. Iron and vitamin supplementation was used by all the pregnant women during the third trimester, and by 35% and 88% during the first and second trimesters, respectively. Analgetics were used on an irregular basis by 12% of the pregnant women, and no correlation to the length of pregnancy could be observed. 9% of the women used medication on a regular basis for reasons such as bronchial asthma, arterial hypertension and hyperthyreosis. Some kind of a symptomatic medication was taken by 43% of the women with no correlation of the length of pregnancy, the most common symptoms needing medication being candidiasis, cough, reflux esophagitis and pregnancy-associated hyperemesis. Tocolytic agents had been given to 8% of the pregnant women. Most tocolytics were used during the end of the second trimester and beginning of the third one. It is concluded that the general use of medicines is quite reasonable in the normal pregnant population in Finland. Iron supplementation should probably be more individualized instead of regular use.

Association of abnormal flow velocity waveforms in the uterine artery with frequency-specific fetal heart rate variability.

The aim of the study was to determine if abnormal flow velocity waveforms in the uterine artery are associated with altered frequency-specific fetal heart rate variability (HRV). Fetuses in the last third of gestation were studied. In seven fetuses the pulsatility index (PI) of the blood flow velocity waveform in the uterine artery was increased (Group II), and in ten fetuses the PI was normal (Group I). Frequency-specific HRV (0.025-0.07 Hz, 0.07-0.13 Hz, 0.13-1.0 Hz) was quantified by power spectral analysis and correlated with the PI in the uterine artery, umbilical artery and the middle cerebral artery. The slow variability dominated the fetal HRV. There was no difference between the groups in the mean frequency-specific variability. In Group II, an increase of the PI in the umbilical artery and a decrease in the middle cerebral artery correlated with an increase of HRV, the increase being greatest at the lowest frequency band.

The need for adjustment of dosage regimen of penicillin V during pregnancy.

OBJECTIVE: To determine whether the normal regimen of dosage of oral penicillin V is relevant during pregnancy. METHODS: Twelve pregnant and six nonpregnant women volunteered for the study. Six women were in the second trimester of pregnancy (mean +/- standard deviation 19 +/- 7 weeks' gestation) and six women were in the third trimester (35 +/- 2 weeks). All of the women took 1 x 10(6) IU phenoxymethylpenicillin orally, and multiple blood and urine samples were obtained. Assays were performed by means of a disk agar diffusion method. The results were compared by Mann-Whitney U test. RESULTS: Compared with nonpregnant women, pregnant women had smaller area under the curve values (433 +/- 93 minutes.IU/mL, P < .05 in the second trimester; 550 +/- 220 minutes.IU/mL in the third trimester) and a shorter half-life (57 +/- 56 minutes in the second trimester; 34 +/- 21 minutes, P < .05 in the third trimester). Plasma and renal clearances were faster in the pregnant women. CONCLUSION: Elimination of penicillin V is enhanced during pregnancy, necessitating either a shorter dosing interval (6-8 hours) or an increased dose with the standard dosing interval.

Cardiovascular autonomic reflexes in mid-pregnancy.

OBJECTIVE: To study the physiological responses to noninvasive cardiovascular autonomic function tests in normal pregnancy. DESIGN: Cardiovascular autonomic responses in 60 women at 22 to 29 weeks gestation and 62 nonpregnant women were investigated using the Valsalva manoeuvre as well as orthostatic, quiet breathing, deep breathing, and isometric handgrip tests. RESULTS: Compared with nonpregnant women, those who were pregnant showed significantly lower heart rate variability during normal breathing and a blunted tachycardic reaction to blowing during the Valsalva manoeuvre. The vagally controlled biphasic heart rate response to standing was also attenuated in the pregnant group. CONCLUSIONS: The cardiovascular responses were blunted in mid-pregnancy indicating a decrease in parasympathetic cardiovascular control.

Effects of short-term thermal stress on plasma catecholamine concentrations and plasma renin activity in pregnant and nonpregnant women.

OBJECTIVE: The purpose of this study was to find out whether the effects of thermal stress on plasma catecholamines and plasma renin activity are altered by pregnancy. STUDY DESIGN: Nonpregnant (n = 15) and pregnant (13 to 14 weeks, n = 23; 36 to 37 weeks, n = 23) healthy women were examined. Samples were taken before the exposure, in the heat chamber (70 degrees C), and during the recovery. The BMDP statistical software was used. RESULTS: The concentration of epinephrine in plasma increased significantly only in the nonpregnant group. The epinephrine concentrations in the pregnancy groups increased most in the subjects who felt discomfort during or after the exposure. Plasma norepinephrine concentrations increased without significant differences between the groups. Plasma renin activity increased in each group, but the increases were significantly lower in the pregnancy groups as compared with the nonpregnant group. CONCLUSIONS: Pregnancy does not alter the thermally induced increase in norepinephrine release. The adrenaline response is mostly dependent on the mental discomfort. The plasma renin activity response to thermal stress is blunted during pregnancy.

Changes in autonomic cardiovascular control in mid-pregnancy.

Spectral analysis of heart rate variability was used to study autonomic nervous control in mid-pregnancy. Fifty women (age 22-36 years) with singleton pregnancies (mean duration of gestation 27.7 weeks) and 39 non-pregnant female controls (age 21-39 years) were studied using controlled breathing and orthostatic tests. During spontaneous breathing the overall heart rate variability was lower in pregnant subjects indicating a decreased parasympathetic tone at rest. The decreased parasympathetic tone probably counts for the increased heart rate in pregnancy. The parasympathetic efferent capacity of autonomic cardiac control was found to be similar in pregnant and non-pregnant subjects, as no difference was seen during controlled breathing in periodic heart rate variability between the groups. Standing up caused a similar change in low frequency and mid-frequency bands in both groups, but high frequency heart rate variability increased in pregnant subjects and decreased in the controls indicating an increased sympathetic tone at rest in mid-pregnancy.

Flow velocity waveforms in uterine and umbilical arteries during submaximal bicycle exercise in normal pregnancy.

Eight healthy women who were not conditioned athletes, at 35-38 weeks' gestation, performed a submaximal bicycle exercise test three times for 4 minutes each with stepwise increases (73 +/- 27, 114 +/- 29, and 161 +/- 16 W) of the work load. The target heart rate at the end of the last load was 170 beats per minute. The systolic-diastolic ratios (S/Ds) of flow velocity waveforms were measured with pulsed color Doppler ultrasound in the uterine and umbilical arteries immediately after each work load and during recovery. The heart rates at the end of each load (133 +/- 3, 156 +/- 3, and 173 +/- 7 beats per minute) corresponded to an average of 70, 83, and 92% of the calculated maximum heart rate. With the subject in the sitting position on the ergometer before exercise, the S/D in the uterine artery was 1.49 +/- 0.09, increasing gradually and significantly during the exercise to the maximum of 2.04 +/- 0.06 at 1 minute of recovery. Heart rate and S/D in the uterine artery correlated significantly (r = 0.58, P less than .01). Although the mean arterial pressure increased significantly during exercise from 92 +/- 6 to 109 +/- 10 mmHg, the significant decrease of the ratio of the mean arterial blood pressure and S/D suggests that the flow in the main uterine artery may decrease during intense exercise. No changes occurred in the S/D of the umbilical artery flow velocity, but the fetal heart rate increased significantly.

Uterine and umbilical flow velocity waveforms in normotensive and hypertensive subjects during the angiotensin II sensitivity test.

The systemic and uterine circulatory effects of angiotensin II infusion in five normotensive and 10 hypertensive subjects at the end of the third trimester of gestation were studied. Color Doppler ultrasonography was used for investigating the systolic/diastolic ratios on flow velocity waveforms in the uterine and umbilical arteries. A significant increase was observed in the systolic/diastolic ratio in the uterine artery in both groups. In normotensive subjects a differential effect of angiotensin II on the systemic diastolic blood pressure and on the systolic/diastolic ratio was observed; the uterine circulation had a slower response and a faster recovery than the maternal diastolic blood pressure. In hypertensive subjects this relative refractoriness to angiotensin II was less marked; the increase in uterine vascular resistance was faster and the recovery slower than in the normotensive group. No changes in the systolic/diastolic ratio in the umbilical artery were observed in either group. These results indicate that the uterine circulation of normotensive subjects is remarkably more refractory to angiotensin II than the circulation of hypertensive subjects.