N.F. Gant’s research while affiliated with University of Texas Southwestern Medical Center and other places

Vascular refractoriness to infused angiotensin II (AII) characterizes normal human and ovine pregnancy. To ascertain whether the refractoriness in the gravid ewe is mediated by either endogenous plasma concentrations of renin and AII or vasomotor reflexes, effects of acute volume expansion (VE) on the pressor response to AII were studied in chronically instrumented nonpregnant and near-term pregnant sheep. Dose-response curves describing the pressor response (delta BP) were determined before and after infusions of 1.0 1 of isotonic saline (NS) or 0.5 1 of 10% dextran (D). In nonpregnant sheep, hematocrit (Hct) and plasma renin activity (PRA) fell in all animals after NS (n = 7) and D (n = 6) (P less than 0.005). After VE with NS and D, delta BP increased at each dose of AII (P less than 0.05). The pressor response to AII in pregnant sheep was not altered by NS although decreases in Hct and PRA were comparable to those in nonpregnant sheep. Baroreceptor responses were not altered. Vascular refractoriness to infused AII in pregnant sheep is not due primarily to changes in plasma concentrations of renin-AII but more likely to another factor, vessel wall refractoriness. In this respect, the ewe is similar to the human.

Vascular refractoriness to the systemic pressor effects of angiotension II (AII) develops normally during human pregnancy. To ascertain if the ewe might provide a suitable animal model to study the mechanisms responsible for this response (unique to pregnancy) we studied this phenomenon in unanesthetized, chronically instrumented nonpregnant and pregnant sheep, 68-143 d gestation. In these studies dose-response curves were established for changes in both mean arterial pressure and uterine blood flow. The pressor response to continuous infusions of AII increases as a function of the dose of AII in both nonpregnant and pregnant animals (P less than 0.001), R = 0.943 and 0.879, respectively. However, the pregnant animals were refractory to the pressor effects of AII, requiring 0.016 microgram of AII/min per kg to elicit a 20 mm HG rise in mean arterial pressure, in contrast to 0.009 for nonpregnant animals. The slope and intercept for the regression lines are different at P less than 0.001. In pregnant animals the dose-response curve for uterine blood flow was also determined. Increases in uterine blood flow were observed at doses of AII less than 0.016 microgram/min per kg, while larger doses resulted in a progressively greater reduction in blood flow. It appears likely that the ewe may serve as an animal model suitable for the further study of the unique pregnancy-modified systemic and uteroplacental vascular responses elicited by AII.

The plasma concentration of deoxycorticosterone (DOC) was determined serially in a large group of primigravid women from 10 weeks' gestation to term. The plasma level of DOC in women whose pregnancies were uncomplicated (n = 44) was 234 +/- 33 pg/ml (mean +/- SE), at 10 to 14 weeks' gestation, a level two times that of nonpregnant subjects. The plasma level of DOC in these women rose to 778 +/- 65 pg/ml at 23 to 26 weeks' gestation, and at term (39 to 42 weeks) was 1,309 +/- 155 pg/ml. The plasma levels of DOC in women (n = 31) who eventually developed pregnancy-induced hypertension (PIH) were similar to those in the women who remained normal at all stages of pregnancy. We also found that, in women with normal pregnancies as well as in all stages of pregnancy. We also found that, in women with normal pregnancies as well as in women destined to develop PIH, the plasma concentration of DOC fluctuated in a manner parallel to that of progesterone throughout gestation; however, changes in the plasma level of DOC did not mirror those of cortisol. These data suggest that excessive plasma levels of DOC are not necessarily associated with the development of PIH. These data also support the view that, in pregnant women, a fraction of circulating DOC may arise via extra-adrenal 21-hydroxylation of progesterone rather than through adrenal secretion.

The plasma concentration of deoxycorticosterone (DOC) was determined serially in a large group of primigravid women from 10 weeks' gestation to term. The plasma level of DOC in women whose pregnancies were uncomplicated (n = 44) was 234 ± 33 pg/ml (mean ± SE), at 10 to 14 weeks' gestation, a level two times that of nonpregnant subjects. The plasma level of DOC in these women rose to 778 ± 65 pg/ml at 23 to 26 weeks' gestation, and at term (39 to 42 weeks) was 1,309 ± 155 pg/ml. The plasma levels of DOC in women (n = 31) who eventually developed pregnancy-induced hypertension (PIH) were similar to those in the women who remained normal at all stages of pregnancy. We also found that, in women with normal pregnancies as well as in women destined to develop PIH, the plasma concentration of DOC fluctuated in a manner parallel to that of progesterone throughout gestation; however, changes in the plasma level of DOC did not mirror those of cortisol. These data suggest that excessive plasma levels of DOC are not necessarily associated with the development of PIH. These data also support the view that, in pregnant women, a fraction of circulating DOC may arise via extra-adrenal 21-hydroxylation of progesterone rather than through adrenal secretion.

During the third trimester of human pregnancy the concentrations of deoxycorticosterone (DOC) in maternal plasma are 4-50 times those in nonpregnant women and men. It has been suggested that the increased amount of DOC in maternal plasma originates in the fetal compartment. We considered an alternate explanation for the high levels of DOC in plasma or near-term pregnant women, viz., that DOC may be derived in part from 21-hydroxylation of maternal plama progesterone. To test this hyposthesis we measured the fractional conversion of plasma progesterone to DOC from the relationship between the 3H:14C ratio of the infused tracers, [3H]progesterone and [14C]-DOC, and the 3H:14C ratio or urinary 3 alpha,21-dihydroxy-5 beta-pregnan-20-one (tetrahydro-DOC). The fractional conversion of plasma progesterone to DOC ([rho](BU)P-DOC), measured in this manner, was 0.007 +/- 0.001 (mean +/- SEM, n = 26) in the subjects of this study. The values for [rho](BU)P-DOC varied widely among subjects (0.002-0.022) but the range of values for [rho](BU)P-DOC was similar among women pregnant with an anencephalic or dead fetus, nonpregnant and adrenalectomized women, and men. The transfer constant of conversion of progesterone to DOC in plasma, [rho](BB)P-DOC, remained constant in a nonpregnant woman during the infusion of nonradiolabeled progesterone at rates of 0-14 mg/h. Based on the results of these studied, we conclude that DOC is formed by extra-adrenal 21-hydroxylation of plasma progesterone and that the rate of formation of DOC by this pathway is proportional to the concentration of progesterone in plasma.

We have suggested that the placental clearance of maternal plasma dehydroisoandrosterone sulfate (DS) through estradiol (E2) formation (PC-DSE2) is reflective of uteroplacental blood flow (F). Clewell and Meschia13 suggested that PC-DSE2 is related to F as follows: Cobs = F(1-e-C/F), where Cobs = PC-DSE2 and C = total placental clearance of maternal plasma DS. This equation contains two unknown quantities, F and C. To solve the equation, Clewell and Meschia assumed that C was constant. Using 19.7 ml/min for C, they allowed PC-DSE2 to vary widely and computed F. Upon finding that F was unrealistically low for some values of PC-DSE2, they concluded that reductions in PC-DSE2 do not reflect alterations in uteroplacental blood flow. In the analysis of the relationship of F to PC-DSE2, it is important to know the value of C. Since the direct measurement of C is not possible at this time, we have evaluated C by measuring the difference between the metabolic clearance rate of DS (MCR-DS) prior to and immediately following delivery. Any change in MCR-DS before and after delivery should be a reflection of the amount of maternal plasma DS cleared by the placenta through all metabolic routes including PC-DSE2, providing nonplacental clearances of maternal plasma DS before and immediately after delivery are the same. We measured MCR-DS and PC-DSE2 in 15 pregnant women within 5 days before delivery and repeated the MCR-DS measurement in these women beginning 90 minutes after delivery. Among these 15 women, C ranged from a low of 4.7 ml/min in a woman with severe pre-eclampsia to a high of 28.5 ml/min in a woman with twins. In addition to the finding that C varied widely, it was also ascertained that PC-DSE2 was positively correlated with C (r = 0.908; p less than 0.001). The finding that low or high values for PC-DSE2, observed in complicated pregnancies, were associated with similar changes in C is suggestive that a change in PC-DSE2 is reflective of a change in uteroplacental blood flow.

The plasma concentrations of progesterone and 5-alpha-pregnane-3,20-dione (5-alpha-dihydroprogesterone) were measured from as early as 12 weeks through 41 weeks of gestation in primigravid women. Two groups of primigravid women were assessed, those with uncomplicated pregnancies and those who developed pregnancy-induced hypertension. Plasma levels of progesterone and 5-alpha-dihydroprogesterone rose progressively throughout gestation in both groups of women. The ratio of the level of progesterone to that of 5-alpha-dihydroprogesterone in individual plasma samples of women with uncomplicated pregnancies was 7.0 from 12 to 15 weeks' gestation while at 35 to 41 weeks' gestation the ratio had declined to 4.6. Similar results were obtained in plasma samples of women who ultimately developed pregnancy-induced hypertension. Since no differences in plasma levels of progesterone or 5-alpha-dihydroprogesterone were detected between primigravid women with uncomplicated pregnancies and those who developed pregnancy-induced hypertension, we conclude that neither progesterone nor 5-alpha-dihydroprogesterone concentrations in plasma are of value in identifying women at risk of developing pregnancy-induced hypertension.

The plasma concentrations of progesterone and 5α-pregnane-3,20-dione (5α-dihydroprogesterone) were measured from as early as 12 weeks through 41 weeks of gestation in primigravid women. Two groups of primigravid women were assessed, those with uncomplicated pregnancies and those who developed pregnancy-induced hypertension. Plasma levels of progesterone and 5α-dihydroprogesterone rose progressively throughout gestation in both groups of women. The ratio of the level of progesterone to that of 5α-dihydroprogesterone in individual plasma samples of women with uncomplicated pregnancies was 7.0 from 12 to 15 weeks' gestation while at 35 to 41 weeks' gestation the ratio had declined to 4.6. Similar results were obtained in plasma samples of women who ultimately developed pregnancy-induced hypertension. Since no differences in plasma levels of progesterone or 5α-dihydroprogesterone were detected between primigravid women with uncomplicated pregnancies and those who developed pregnancy-induced hypertension, we conclude that neither progesterone nor 5α-dihydroprogesterone concentrations in plasma are of value in identifying women at risk of developing pregnancy-induced hypertension.