Role of volume in the regulation of vasopressin secretion during pregnancy in the rat.

We previously observed that osmoregulation and the osmotic threshold for antidiuretic hormone secretion were altered during pregnancy in Sprague-Dawley rats and the present study evaluated the influence of volume on arginine vasopressin (AVP) release during gestation in this species. Basal plasma osmolality (Posm) and intravascular volume were 297 +/- 3 mosmol/kg and 16.2 +/- 1.2 ml in virgin animals compared with 290 +/- 2 mosmol/kg and 20.2 +/- 2.3 ml in 14-d pregnant rats and 287 +/- 3 mosmol/kg and 25.2 +/- 2.3 ml in 21-d (near-term) pregnant rats (P less than 0.001, each pregnant group vs. virgin). Isosmotic volume depletion was produced by intraperitoneal polyethylene glycol. Volume decreased from 1 to 26% and blood pressure remained stable during decrements as high as 16%. Plasma AVP (PAVP) did not rise significantly in either group of pregnant animals or virgin controls until blood volume depletion reached 6-7%, after which levels rose in a similar exponential manner in virgin, 14-d, and 21-d pregnant animals. In terms of absolute changes, however, PAVP in gravid rats started to increase when intravascular volume was still considerably greater than basal blood volume in the nonpregnant controls. Other experiments, where Posm was increased by intraperitoneal hypertonic saline, reconfirmed that the osmotic threshold for AVP secretion was reduced congruent to 10 mosmol/kg during pregnancy and that AVP release was stimulated by increments in body tonicity as small as 1-2%. In parallel studies, blood volume contraction and increases in Posm were evoked by intraperitoneal polyethylene glycol dissolved in hypertonic saline and results compared with animals receiving intraperitoneal saline alone. Decrements in volume (congruent to 7%), which alone would increase PAVP minimally, increased the sensitivity of the secretory response to changes in osmolality two- to three-fold, an effect which was similar in virgin and gravid animals. Finally, restricting water intake of pregnant rats to that of virgins on days 16-20 of gestation led to suboptimal volume expansion, hypertonicity, and an exaggerated increase in PAVP. These results demonstrate that despite an intravascular space which at term is nearly twice that of virgin rats, pregnant animals secrete AVP in response to fractional volume depletion in a manner similar to nonpregnant controls; that is, the relationship between total blood volume and AVP secretion is altered during gestation such that the expanded blood volume is recognized as normal.

Changes in the metabolic clearance of vasopressin and in plasma vasopressinase throughout human pregnancy.

Metabolic clearance rates (MCR) of arginine vasopressin (AVP) were measured serially in five women starting before conception, during gestational weeks 7-8 (early), 22-24 (middle), and 36-38 (late pregnancy), and again 10-12 wk postpartum. Hormonal disposal rates were determined after water loading to suppress endogenous AVP release using a constant infusion method designed to achieve three different steady-state concentrations of plasma AVP (PAVP) on each test occasion. Dose schedules were altered in mid- and late pregnancy to obtain comparable AVP levels at each stage of the protocol. Prehydration decreased plasma osmolality sufficiently to suppress AVP release, as circulating AVP-neurophysin measured serially in three of the women was undetectable. The MCR of AVP was similar before conception (0.75 +/- 0.31, 0.79 +/- 0.34, and 0.76 +/- 0.28 liters/min at PAVP of 2.6 +/- 1.9, 4.7 +/- 2.4, and 8.3 +/- 3.9 pg/ml), in early pregnancy (0.89 +/- 0.34, 0.97 +/- 0.04, and 0.95 +/- 0.40 liters/min at PAVP of 2.2 +/- 2.1, 3.9 +/- 3.2, and 7.9 +/- 3.4 pg/ml), and postpartum (0.70 +/- 0.21, 0.69 +/- 0.24, and 0.75 +/- 0.20 liters/min at PAVP 3.5 +/- 1.8, 5.1 +/- 3.7, and 9.1 +/- 4.2 pg/ml). Values at mid-pregnancy (2.8 +/- 1.3, 3.0 +/- 1.2, and 2.7 +/- 1.2 liters/min at PAVP 2.3 +/- 2.2, 4.0 +/- 3.6, and 7.7 +/- 3.9 pg/ml) and late pregnancy (3.2 +/- 1.4, 3.3 +/- 1.4, and 2.9 +/- 1.2 liters/min at PAVP 1.9 +/- 2.0, 3.8 +/- 2.6, and 7.4 +/- 4.1 pg/ml) increased 3-4-fold (all P less than 0.01). Plasma vasopressinase, undetectable at 7-8 gestational wk, increased markedly by mid- and slightly more by late gestation. Finally, relationships between PAVP and urine osmolality were similar before, during, and after pregnancy. We conclude that marked increments in the MCR of AVP occur between gestational weeks 7 and 8 and mid-pregnancy, which parallel the period of greatest rise in both trophoblastic mass and plasma vasopressinase. There was no evidence of a renal resistance to AVP during gestation.

Prior feeding alters the response to the 50-g glucose challenge test in pregnancy. The Staub-Traugott effect revisited.

OBJECTIVE: To examine the effect of prior meal ingestion on the glucose, insulin, and C-peptide response to a 50-g glucose challenge test in the third trimester of pregnancy. RESEARCH DESIGN AND METHODS: Ten pregnant women with gestational diabetes mellitus and 12 nondiabetic pregnant control subjects matched for age and weight underwent a 50-g glucose challenge test on three occasions within a 2-wk period, in random order. On one occasion the test was administered in the fasting state (fasting glucose challenge test), on a second occasion the test was administered 1 h after ingestion of a standard mixed meal (1-h postprandial study), and on a third occasion the test was administered 2 h after ingestion of a standard mixed meal (2-h postprandial study). RESULTS: In the control subjects, the plasma glucose level 1 h after ingestion of 50 g of glucose was higher in the fasting study (7.8 +/- 0.4 mM, 7 of 12 subjects with glucose > or = 7.8 mM) than in the 1-h postprandial study (6.7 +/- 0.3 mM, 3 of 12 subjects with glucose > or = 7.8 mM) and the 2-h postprandial study of (6.3 +/- 0.4 mM, 3 of 12 with glucose > or = 7.8 mM) (P < 0.01). In the postprandial studies of control subjects, insulin and C-peptide levels were higher at the time of ingestion of the 50 g of glucose, but the early (1 h) insulin secretory response was less than in the fasting study. In the diabetic patients, glucose levels 1 h after 50-g glucose ingestion were similar in the fasting study (10.5 +/- 0.4 mM, no subjects with glucose value < 7.8 mM) and the 1-h postprandial study (11.0 +/- 0.6 mM, 1 subject with glucose < 7.8 mM), but was lower in the 2-h postprandial study (9.3 +/- 0.3 mM, 1 subject with glucose < 7.8 mM) (P < 0.03). In contrast to the control subjects, the insulin secretory response to 50 g of oral glucose was greater in the two postprandial studies than in the fasting study. CONCLUSIONS: We have reached the following conclusions. 1) In nondiabetic gravidas, plasma glucose concentrations 1 h after ingestion of a 50-g oral glucose load are higher if administered in the fasting state compared with the postprandial state. 2) During normal pregnancy the Staub-Traugott Effect, i.e., improved glucose disposal after successive glucose load administrations, occurs and appears to be caused by mechanisms other than enhanced insulin secretion with successive glucose loads. 3) The effect of the prandial state on plasma glucose response to the 50-g glucose challenge test used to screen for gestational diabetes mellitus may be of sufficient magnitude to significantly alter the operating characteristics, i.e., sensitivity and specificity, of this test.

Reducing unnecessary coagulation testing in hypertensive disorders of pregnancy.

OBJECTIVE: To estimate the magnitude of laboratory testing for hypertension in pregnancy and determine whether abnormalities in prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen can be predicted by results of common, less expensive tests. MATERIALS AND METHODS: Laboratory records were searched and charts were reviewed to identify gravidas tested for hypertension and to exclude conditions producing coagulopathy. Contingency tables were constructed to assess the ability of the platelet count, lactate dehydrogenase, and transaminases to predict coagulation test results. RESULTS: Preliminary data on 73 gravidas found that a platelet count plus a lactate dehydrogenase test best predicted coagulation abnormalities. Results on another 732 gravidas indicated that coagulation tests were obtained in about 30%. No patient had a PT greater than 18 seconds, two had an aPTT greater than 40 seconds, and three had fibrinogen levels less than 200 mg/dL. The combination of a normal platelet count plus a normal lactate dehydrogenase had a negative predictive value of 100% for clinically significant abnormalities of PT and aPTT, and 99% for significant abnormalities of fibrinogen. CONCLUSIONS: Substantial coagulation testing was done on gravidas evaluated for a hypertensive disorder even though the prevalence of clinically significant abnormalities was low. Laboratory evaluation of patients suspected of having preeclampsia need not include a PT, aPTT, or fibrinogen test when there is no evidence of bleeding or of a condition that could produce coagulopathy and when the platelet count and lactate dehydrogenase level are both normal.

Recurrent diabetes insipidus associated with pregnancy: pathophysiology and therapy.

Diabetes insipidus during pregnancy is an uncommon medical problem. We present a woman who developed transient central diabetes insipidus during two successive pregnancies. A water deprivation study with plasma arginine vasopressin concentrations confirmed the diagnosis and established the efficacy of 1-desamino-8-d-arginine-vasopressin (dDAVP). The patient was then successfully and safely treated through the second pregnancy with dDAVP.

Medical evaluation of the pregnant patient requiring nonobstetric surgery.

This article provides a summary of currently available information from a broad range of disciplines aimed at guiding the physician caring for the pregnant patient who requires nonobstetric surgery. An understanding of the anatomic and physiologic alterations that occur during pregnancy will allow such procedures to be accomplished with morbidity and mortality approaching those of nonpregnant surgical patients. The presence of the fetus does impose some restraint; however, this should rarely impair appropriate diagnosis and treatment of maternal disease. This obtains from the broad range of diagnostic and therapeutic alternatives available, and from the fact that what is beneficial for maternal health is generally best for the fetus.

Failed appointments. Who misses them, why they are missed, and what can be done.

Failure to keep appointments is disruptive to the health care delivery system in several ways. Rates of missed appointments in a variety of practice settings demonstrate a significant problem. The patient most likely to fail to keep a given appointment is one who is young, comes from a low socioeconomic group, has a large, unstable family, and has previously broken appointments. In addition, this patient will most likely have no significant ongoing relationship with a single physician, may have been referred from an emergency room, will have been scheduled for his or her appointment at a distant time, may well have forgotten about the appointment or thought it was scheduled for another time, and will feel little sense of urgency about keeping the appointment. Several effective methods to reduce appointment-breaking behavior are discussed. Mailed appointment reminders are both effective and cost-efficient. Improved communication between patient and physician combined with personal interest and attention an produce a positive effect on the appointment-keeping behavior of a patient. Finally, the pragmatic details of appointment scheduling can be altered to reduce the disruptive effect of the missed appointment by such methods as predictive overbooking based on individual patient characteristics, use of the modified wave scheduling technique, and elimination of the automatic reappointing of patients who have previously broken appointments.

Volume homeostasis during pregnancy in the rat.

This article reviews alterations in volume and sodium handling during rat pregnancy, noting similarities and contrasts to events in human gestation. Gravid rodents undergo extracellular and plasma volume increases of 50% to 70%, and these changes accompany a marked cumulative sodium retention shared by both dam and fetuses. Pregnancy alters several factors, with opposing effects on renal salt handling; however, mechanisms by which gestational sodium accumulation and volume expansion are achieved remain obscure. Furthermore, despite substantial increases in absolute blood volume, considerable uncertainty exists as to how this volume is sensed, particularly during the final gestational week when a rapid increase in volume is associated with decreases in peripheral resistance and BP. Attempts to assess "effective" intravascular volume by measuring responses to intravenous (IV) or oral sodium loading or to chronic mineralocorticoid administration indicate that pregnant and nonpregnant rats respond similarly, suggesting that such animals sense their volume as normal. In contrast, when salt-restricted, gravid rats fail to expand their plasma volume normally; this relative hypovolemia activates mechanisms leading to free water retention and pathologic hyponatremia, responses not observed in virgin animals.

The syndrome of preeclampsia.

Preeclampsia has traditionally been viewed as one of several forms of hypertension complicating pregnancy. More recently, the multisystem nature of this unique gestational disorder has been emphasized. Pathophysiologic events, including abnormal placentation and heightened vascular reactivity, may occur weeks or months prior to clinical recognition of the disease. Although most frequently presenting as hypertension and proteinuria, hepatic (abdominal pain and elevation of transaminases) and hematologic (intravascular hemolysis and thrombocytopenia) involvement may be important features of the disease. Current theories suggest that multiorgan dysfunction may be caused by widespread vascular endothelial dysfunction, vasospasm, and variable activation of coagulation mechanisms. Pending delivery, which is the only definitive therapy for preeclampsia, maternal complications of intracerebral hemorrhage and eclampsia may be prevented with judicious use of antihypertensive medication (e.g., hydralazine) and magnesium sulfate, respectively. Finally, data from a number of small trials suggest that low-dose aspirin (60-100 mg/d) may reduce the incidence of preeclampsia in patients at high risk without adversely affecting the fetus or newborn; however, it is recommended that aspirin not be used as a routine prophylactic intervention until publication of results of several ongoing large multicenter trials, which will help to more fully clarify the benefits and risks of this approach.

The pregnant surgical patient: medical evaluation and management.

Nonobstetric disease requiring surgery may complicate pregnancy and jeopardize maternal and fetal well-being. Surgery may be safely done if the physician is aware of anatomic and physiologic alterations during gestation that necessitate an altered approach to diagnosis and management. Fetal exposure to all diagnostic and therapeutic agents should be minimized, particularly during organogenesis. However, the risk to the fetus of diagnostic irradiation is justifiable when information essential to maternal health is likely to be obtained. Furthermore, the broad range of available antibiotic, analgesic, and anesthetic agents provide the physician with options for treatment that have an acceptable degree of risk to fetal health. Anesthesia and surgery are tolerated considerably better by the fetus than is maternal hypotension, hypoxia, or sepsis. When an operative procedure is urgently or emergently indicated, pregnancy should not delay timely intervention.

Effect of oral protein loading on renal hemodynamics in human pregnancy.

Glomerular filtration rate (GFR) and ERPF increase approximately 50% in human pregnancy. To determine if pregnant women have additional "renal reserve," inulin and p-aminohippurate clearances (Cin, CPAH) were measured in maximally hydrated women before and after a 300-g steak meal, once during late gestation, and again > or = 3 mo postpartum. Protein loading increased Cin [106 +/- 5 (SE) to 119 +/- 4 ml/min, P < 0.003], but not CPAH (587 +/- 35 to 624 +/- 32 ml/min, NS) in the nonpregnant state, but neither clearance was altered during gestation (Cin: 156 +/- 7 to 160 +/- 9.6 ml/min, NS; CPAH: 831 +/- 36 to 899 +/- 37 ml/min, NS). A natriuresis occurred only postpartum (+142 mu eq/min, P < 0.02), which could be explained by the increased GFR alone, since indexes of filtrate delivery and reabsorption (V/GFR, CH2O/GFR, CH2O/V) and fractional sodium excretion changed little. Dopamine excretion, uninfluenced by protein, did not correlate with increments in GFR. A carbohydrate meal (time controls) had no effect on the above described parameters. We make the following conclusions. If protein and pregnancy achieve hyperfiltration by similar mechanisms, these pathways appear "exhausted" in gestation. Also, oral protein loading does not measure maximal renal reserve, since basal GFR in late gestation was substantially greater than that measured after protein feeding in nonpregnant subjects.

Osmoregulation in pseudopregnant and prolactin-treated rats: comparison with normal gestation.

Osmoregulation was studied throughout rodent pregnancy focusing on the importance of the fetoplacental unit and prolactin in the observed alterations. Plasma osmolality (Posmol) and plasma sodium (PNa), similar in 8-day gravid and virgin Sprague-Dawley rats, decreased significantly by gestational day 10, reaching a nadir 8-10 mosmol/kg and 3-5 meq/l, respectively, below virgin levels by day 14 (both P less than 0.001). Despite this, plasma arginine vasopressin (PAVP) was measurable and similar in all pregnant and virgin groups. Osmotic thresholds for arginine vasopressin (AVP) secretion, similar in 8-day gravid and virgin rats, decreased 7.7 and 10.7 mosmol/kg in 12- and 14-day pregnant rats, respectively (both P less than 0.001). In contrast, Posmol decreased less than 2 mosmol/kg in 12- to 14-day pseudopregnant animals. When pseudopregnancy was prolonged to 18 days by prior hysterectomy, Posmol was only 2.6 mosmol/kg below that of cycling, hysterectomized controls. In other studies 14 days of hyperprolactinemia evoked by estradiol or treatment with ovine or rat prolactin had minimal effect on Posmol. We conclude that parallel decrements in Posmol and osmotic thresholds for AVP release occur during early rodent pregnancy, alterations that cannot be explained by gestational increases in circulating prolactin. In addition, the failure of pseudopregnancy. to mimic the hypotonicity of gestation suggests an important role for the fetoplacental unit in the osmoregulatory changes of rat pregnancy.

Effect of sinoaortic denervation on pressor responses in pregnant rats.

We tested the hypothesis that augmented arterial baroreflex activity contributes to attenuation of pressor responses in intact pregnant animals by comparing changes in blood pressure and heart rate during infusions of angiotensin II, phenylephrine, and vasopressin in chronically instrumented pregnant and virgin rats approximately 5 wk after sinoaortic denervation (SAD) or sham surgery. Baseline mean arterial pressure was significantly lower in pregnant animals in both the sham-operated (pregnant 91.7 +/- 1.7 mmHg, virgin 103.7 +/- 2.5 mmHg) and SAD states (pregnant 107.3 +/- 4.0 mmHg, virgin 114.1 +/- 4.0 mmHg). Pressor responses to all three agents were significantly blunted in pregnant animals compared with similarly treated virgins, with the magnitude of attenuation similar in both sham and SAD states. Heart rate decreased similarly in reflex-intact pregnant and virgin animals during pressor infusions. These findings suggest that attenuated pressor responses in the pregnant rat are due primarily to mechanisms other than augmentation of arterial baroreflex activity and are consistent with a generalized reduction in vascular sensitivity during gestation.

Indirect blood pressure measurement in pregnancy: Korotkoff phase 4 versus phase 5.

Controversy exists regarding which Korotkoff phase should be used to estimate diastolic blood pressure during pregnancy, some authorities recommending phase 5 (disappearance of sounds) and others suggesting phase 4 (muffling). Available data indicate that Korotkoff phase 5 more closely approximates true intraarterial diastolic pressure in pregnant women. Nonetheless, it has been suggested that phase 5 is unmeasurable in a significant number of gravid women, making this end point less desirable. However, studies examining this issue indicate that Korotkoff phase 5 is determinable in more than 90% of gravid women and that the incidence of an indeterminable phase 4 is at least as great as that for phase 5. Moreover, there appears to be greater observer variability in the measurement of phase 4 compared with phase 5. We conclude that available evidence supports recommendations for the use of Korotkoff phase 5 as the preferred end point to estimate diastolic blood pressure during pregnancy. In those few patients having very low or indeterminate phase 5 determinations, both phase 4 and phase 5 should be recorded and the former used to guide patient management. An alternative strategy is to record both phases in all gravid women beginning at the first prenatal visit so that baseline phase 4 values are available in the event that phase 5 becomes indeterminate.

Osmotic and volume control of vasopressin release in pregnancy.

This article, a review of factors controlling vasopressin (AVP) release in pregnancy, extends our contribution to a symposium in this journal published in 1987 (vol X, pp 270-275). Body tonicity decreases (approximately 10 mOsm/kg) very early in pregnancy due to decrements in the osmotic thresholds for AVP release and thirst. In addition, the metabolic clearance rate (MCR) of AVP markedly increases between gestational week 10 and midpregnancy, and is paralleled by the appearance and increase of circulating cystine aminopeptidase (vasopressinase), while the MCR of 1-deamino-8-D-AVP (DDAVP), an analogue resistant to inactivation by the enzyme, changes little in pregnancy. These increases (MCR of AVP and plasma vasopressinase) may explain certain syndromes of transient diabetes insipidus (DI) that complicate gestation. Finally, mechanisms responsible for the altered osmoregulation in pregnancy are obscure, but chorionic gonadotropin may be involved in the changes during human gestation.

Effect of autonomic blockade on pressor responses to vasopressin in pregnant rats.

OBJECTIVE: We tested the hypothesis that gestational changes in reflex neural control of the heart and vasculature contribute to altered cardiovascular responses to vasopressin during pregnancy. STUDY DESIGN: Changes in mean arterial pressure, cardiac output, total peripheral resistance, and heart rate were measured in response to constant infusion of arginine vasopressin (0.15 to 2.5 mU/kg/min) in conscious pregnant and virgin rats (n = 9) with total autonomic blockade plus restoration of baseline hemodynamics by norepinephrine infusion. RESULTS: Resting cardiac output was 40% higher and total peripheral resistance 30% lower in pregnant animals (p < 0.01). Constant infusion of arginine vasopressin evoked equivalent changes in mean arterial pressure in both groups, but the respective contributions of cardiac output and total peripheral resistance to mean arterial pressure differed between groups. Cardiac output was unchanged and the increase in total peripheral resistance was significantly blunted in pregnant vs virgin rats during arginine vasopressin infusion. Control data in nonblocked revealed similar pressor responses to arginine vasopressin in gravid compared with virgin rats but no differences in the contributions of cardiac output and total peripheral resistance to the change in mean arterial pressure. CONCLUSION: These findings suggest that neural modulation of arginine vasopressin-induced hypertension is altered during pregnancy and are consistent with a reduction in intrinsic vascular sensitivity to arginine vasopressin during gestation.

Pressor effect of endothelium-derived relaxing factor inhibition in conscious virgin and gravid rats.

We used pressor responses to N-methylarginine (NMA), a specific inhibitor of endothelium-derived relaxing factor (EDRF) biosynthesis, to assess the contribution of EDRF to control of basal blood pressure in conscious, chronically instrumented virgin and gravid rats. Hypotheses were that NMA would raise blood pressure in conscious animals in spite of intact cardiovascular reflexes and that differing effects in virgin and pregnant animals would reveal contributions of EDRF to the physiological vasodilation of pregnancy. Basal mean arterial pressure (MAP) and heart rate (HR) were 106 +/- 12 mmHg and 394 +/- 27 beats/min (n = 31) in virgin and 102 +/- 8 mmHg and 378 +/- 18 beats/min (n = 14) in gravid rats. After NMA (150 mg/kg iv), increments in MAP and decreases in HR were similar in each group (virgin, delta MAP = 38 +/- 12 mmHg, delta HR = -65 +/- 27 beats/min, n = 14; gravid, delta MAP = 33 +/- 8 mmHg, delta HR = -63 +/- 20 beats/min, n = 6). Pretreatment with excess L-arginine reduced pressor responses to NMA by 80% in both pregnant and virgin animals. In contrast, L-arginine had no significant effect on the pressor response to phenylephrine (6.4 mg/kg iv). EDRF contributes importantly to regulation of basal blood pressure in conscious animals, and pregnancy does not alter the pressor effect of EDRF inhibition in the rat.

Effect of ovarian sex steroids on osmoregulation and vasopressin secretion in the rat.

Effects of sex steroids on osmoregulation were studied in intact and ovariectomized Sprague-Dawley rats treated for 2 wk with subcutaneously implanted hormone pellets containing 0.5 mg 17 beta-estradiol (E2) alone (group 1) or combined with 50 mg progesterone (PG; group 2) and 5.0 mg E2 alone (group 3) combined with PG (group 4). An additional group (5) of animals was given 14 daily injections with 100 micrograms/100 g body weight of E2. Controls for each group received vehicle alone. There were no alterations in basal plasma osmolality (Posmol) or vasopressin (PAVP), except for group 3 in which a small (2.5 mosmol/kg) decrement in Posmol was observed. However, mean PNa was decreased (0.9-3.4 meq/l) in hormone-treated rats, and alterations in Pglucose and/or Purea could not explain the Na-osmolal discrepancy. Intraperitoneal hypertonic saline resulted in stepwise increases in both Posmol and PAVP. Regression analysis of PAVP on Posmol demonstrated similar osmotic thresholds for AVP release in estrogen and control rats, but the slope (sensitivity of the response) was significantly (P less than 0.005) greater in hormone-treated animals. In contrast, the PAVP response to isosmotic volume depletion was not altered by estrogen. The enhanced response to osmotic stimuli could not be explained by alterations in plasma volume or pituitary AVP content and differed from PAVP -Posmol relationships observed by us previously in gravid rats. In other experiments Posmol and PAVP were similar during all stages of the estrus cycle, while Posmol was approximately equal to 10 mosmol/kg lower in 21-day gravid rats. These data demonstrate that, although estradiol has little effect on basal osmoregulation or hemodynamically mediated AVP release, PAVP responses to osmotic stimuli are markedly enhanced. These osmoregulatory effects, however, differ from those observed during rodent gestation.