Effect of angiotensin II on uterine and systemic vasculature in pregnant sheep.

The response of uteroplacental blood flow (UBF) to angiotensin II is controversial. Moreover, the relationship of the uterine and systemic responses to infused angiotensin II is not well understood. Thus, in eight chronically instrumented, near-term pregnant sheep, we have determined the relationships between the dose and duration of constant systemic infusions of angiotensin II ([Val5] ANG II) and changes in UBF, uterine vascular resistance (UVR), mean arterial pressure (MAP), and systemic vascular resistance (SVR). [Val5] ANG II caused dose-dependent increases in UVR and MAP at all doses studied (P less than 0.05). The response in UBF was bidirectional, with increases at doses less than or equal to 1.15 microgram/min and decreases at greater than or equal to 2.29 micrograms/min (P less than 0.05). Increases in UBP occurred when the relative rise (delta) in MAP greater than delta UVR, whereas UBF was unchanged when delta MAP = delta UVR and decreased when delta MAP less than delta UVR. SVR also rose in a dose-dependent fashion (P less than 0.05); delta SVR was greater than delta UVR at doses less than or equal to 2.29 micrograms [Val5] ANG II/min (P less than 0.01). In studies of the effect of duration of [Val5] ANG II infusions, UBF increased at all doses during the 1st min, followed by stabilization at 4--5 min, with eventual decreases at doses greater than or equal to 2.29 micrograms/min and increases at doses less than 2.29 micrograms/min. The relationship between the changes in MAP and UVR to the response of UBF was as noted above. It is evident that (a) [Val5] NAG II is uterine vasoconstrictor, (b) changes in UBF are dependent upon relative changes in perfusion pressure and UVR, which in turn are dependent upon both the dose and duration of a [Val5] ANG II infusion, and (c) the uteroplacental vasculature is relatively refractory to the vasoconstricting effects of low doses of [Val5] ANG II.

Antihypertensive drugs in pregnancy.

When mean arterial pressure exceeds 140 mmHg (equivalent to 180/120), there is a significant risk of maternal cerebral vascular damage. Therefore it is recommended that blood pressures greater than 170/110 should be treated with urgency, aiming to maintain the blood pressure at all times at less than 170/110 but not lower than 130/90. Parenteral hydralazine is effective and safe therapy. Labetalol (intravenously or orally) appears to be as effective and as safe, and causes fewer troublesome side effects; however, clinical experience of its use is more limited, particularly in relation to its safety for the fetus and neonate. Delivery of the fetus is usually the definitive management of severe hypertension in pregnancy. However, this action may not reduce the blood pressure immediately. After initial treatment with rapid-acting agents, it is often advantageous to maintain control of arterial pressure with ongoing oral therapy (methyldopa, labetalol). In addition to the protective effect on the mother, such therapy may allow delivery of the fetus to be deferred; this should be considered only if the fetus is significantly premature (e.g., less than 34 weeks), there is no other evidence of maternal or fetal distress, and there can be meticulous monitoring of the maternal and fetal state proceeding to prompt delivery if deterioration occurs. The indications for treatment of mild or moderate hypertension in pregnancy are less clear. Severe hypertensive episodes can be reduced by several drugs (methyldopa, labetalol, beta-blockers). Methyldopa appears to reduce the small risk of mid-trimester abortions seen in association with early hypertension. Other benefits may be possible with other individual drugs; however, none of these have been found consistently in controlled studies to date. There seems, therefore, to be no definite indication for treatment of mild hypertension in pregnancy; treatment of moderate hypertension may be reasonable but its value is unproved at present. Antihypertensive drugs are valuable in pregnancy to reduce the risks directly due to elevated blood pressure. These drugs are not expected to affect the evolution of preeclampsia nor to treat the other complications of this condition.

Role of alpha-receptors in estrogen-induced vasodilation in nonpregnant sheep.

Estradiol-17 beta (E2) produces vasodilation in several systemic vascular beds, but most extensively in the nonpregnant uterus. It has been postulated that E2 induces this vasodilation via blockade of vascular alpha-adrenergic receptors. This hypothesis was tested in six chronically instrumented, nonpregnant sheep by comparing the systemic and uterine hemodynamic responses to intravenous E2, to an alpha-adrenergic receptor blocker, phentolamine, and to both agents given together. Uterine blood flow (UBF) increased significantly after E2 administration, from 20 +/- 7 to 233 +/- 37 (SE) ml/min. In contrast, phentolamine had no detectable effect on UBF or on the UBF response to E2 when both were given together. Similar contrasting responses were observed in the effects of E2 and/or phentolamine on the systemic vasculature. When responses to alpha-agonists were evaluated, there was no evidence of alpha-blockade following E2 despite the substantial vasodilation; in contrast, alpha-blockade was present during phentolamine administration when no vasodilation was noted. Therefore, we conclude that E2-induced vasodilation in chronically instrumented sheep is not mediated through blockade of vascular alpha-adrenergic receptors.

Systemic and uterine responsiveness to angiotensin II and norepinephrine in estrogen-treated nonpregnant sheep.

Pregnancy is associated with uterine and systemic vasodilation and reduced vascular reactivity to angiotensin II and perhaps norepinephrine. The uteroplacental vasculature is relatively refractory to angiotensin II but very sensitive to norepinephrine. To investigate the possible role of the high levels of estrogen in pregnancy mediating these hemodynamic changes, we examined systemic and uterine vascular responsiveness to angiotensin II and norepinephrine in eight chronically instrumented nonpregnant sheep treated with 17 beta-estradiol. In these animals, 17 beta-estradiol produced significant systemic and uterine vasodilation without changing arterial pressure; cardiac output increased from 5.3 +/- 0.3 to 6.7 +/- 0.4 L/min, and uterine blood flow increased from 26 +/- 3 to 218 +/- 13 ml/min (mean +/- SE). Treatment with 17 beta-estradiol reduced the increases in systemic vascular resistance produced by angiotensin II and norepinephrine by 25% and 35%, respectively. After 17 beta-estradiol treatment, the uterine vascular responses were compared to the systemic vascular responses; the uterine responses to angiotensin II were only half the systemic responses, whereas the uterine responses to norepinephrine were six times greater than the systemic responses and were associated with decreases in uterine blood flow of 35% to 40%. These hemodynamic features of nonpregnant sheep treated with estrogen are strikingly similar to previous observations in sheep during pregnancy.

Doppler ultrasound in pregnancies with hypertension.

Doppler studies of the arcuate and umbilical arteries were performed longitudinally commencing at 24 weeks or less, in 29 pregnant women with chronic hypertension. The hypothesis was that pregnant women with chronic hypertension who develop superimposed gestational proteinuric hypertension and/or deliver small for gestational age babies are those who have abnormal arcuate and/or umbilical flow velocity waveforms. Abnormal arcuate waveforms occurred in 7 women and abnormal umbilical waveforms in 12. Nine babies were small for gestational age, and 6 of them had abnormal arcuate waveforms. Abnormal arcuate waveforms were significantly associated with the delivery of a small for gestational age baby (p = .001) and identified those babies where early delivery was necessary for fetal reasons. All small for gestational age babies had abnormal umbilical waveforms. Superadded gestational proteinuria (or preeclampsia) occurred in 8 pregnancies, however, only 3 had abnormal arcuate waveforms. An abnormal arcuate waveform did not predict the later development of gestational proteinuria. An abnormal umbilical waveform however, was associated with the subsequent development of gestational proteinuria. We consider that these findings need to be confirmed in a larger study.

Uterine and nonuterine vascular responses to angiotensin II in ovine pregnancy.

The uteroplacental vasculature is more refractory to angiotensin II (ANG II) than the systemic vasculature as a whole. To ascertain the differences in responses between reproductive and nonreproductive tissues that account for this, we infused ANG II (0.573, 5.73, and 11.5 micrograms/min) in pregnant sheep (137 +/- 5 days of gestation) and monitored arterial pressure (MAP), heart rate, and uterine blood flow (UBF); cardiac output and regional blood flows were measured with radiolabeled microspheres. Dose-dependent changes in MAP, UBF, and systemic (SVR) and uterine (UVR) vascular resistance occurred (P less than 0.05); systemic responses exceeded uterine (P less than 0.05), except with 11.5 micrograms/min, when % delta UVR = % delta SVR, % delta UVR greater than % delta MAP, and UBF fell 29%. Although a dose-dependent rise in placental resistance occurred, blood flow was unaffected except at 11.5 micrograms ANG II/min, falling 16.8 +/- 3.5% (P = 0.059). In contrast, endometrial perfusion decreased 68 +/- 4.2 and 81 +/- 1.8% (P less than 0.01) with 5.73 and 11.5 micrograms ANG II/min, respectively. Myometrial responses were intermediate, thus placental flow increased from 75 to greater than 90% of total UBF. Adipose, renal, and adrenal glands were extremely sensitive to ANG II, with blood flows decreasing maximally at 0.573 micrograms/min (P less than 0.05). Maximum adipose vascular resistance occurred at 0.573 micrograms/min, greater than 400% (P less than 0.001), exceeding responses in all tissues (P less than 0.05). The placenta is less responsive to ANG II than other uterine and most nonreproductive tissues, resulting in preferential maintenance of uteroplacental perfusion and protecting the fetus from the effects of this vasoconstrictor.

The pressor response to angiotensin II: the roles of peripheral and cardiac responses in pregnant and nonpregnant sheep.

A reduced pressor response to infused angiotensin II has been observed in pregnancy. Although this has been considered to reflect reduced sensitivity of the peripheral vasculature to angiotensin II, it has also been suggested that the reduced pressor response is due to a fall in cardiac output during infusion of angiotensin II in pregnancy. In the present study we investigated the hemodynamic responses to infused angiotensin II in chronically instrumented, pregnant and nonpregnant sheep. We measured changes in cardiac output and systemic vascular resistance and related these changes to the increase in mean arterial pressure. The response in systemic vascular resistance to angiotensin II was substantially reduced in pregnant sheep. During angiotensin II infusion cardiac output fell in both groups, but the effect of the fall in cardiac output in reducing the pressor response was greater in nonpregnant animals. Thus, it appears that the reduced pressor response to angiotensin II in pregnant sheep is due to reduced systemic vascular responsiveness and not to differences in cardiac output responses.

Effect of hypertonic saline on vascular responses to angiotensin II in pregnancy.

Refractoriness to infused angiotensin II is characteristic or normal human and ovine pregnancy; the mechanisms responsible are unclear. In this study, we sought to ascertain in gravid sheep whether hypertonic saline solution alters the vascular responses to angiotensin II, as in gravid women, and to compare the responses of the systemic and uteroplacental vasculature. Dose-response curves were determined. Mean arterial pressure and systemic vascular resistance increased in a dose-dependent fashion before and after hypertonic saline solution; responses were greater after hypertonic saline solution (p less than 0.01). Responses of cardiac output, heart rate, uterine vascular resistance, and uterine blood flow also were dose-dependent, but were unchanged after hypertonic saline solution. Plasma renin activity fell 45% after hypertonic saline solution. Treatment with hypertonic saline solution results in increased pressor responses to angiotensin II that are not a reflection of altered baroreceptor or chemoreceptor reflexes or of the response in the uteroplacental vascular bed. Rather, the increased systemic vascular responsiveness to angiotensin II after hypertonic saline solution appears to be a reflection of other mechanisms, such as alterations in vessel wall dynamics or receptor affinity.

Metabolic clearance of angiotensin II in pregnant and nonpregnant sheep.

Reduced vascular responsiveness to infused angiotensin II (ANG II) has been observed during pregnancy. It has been proposed that infusions produce lower circulating concentrations of ANG II in pregnancy, due to an increase in the metabolic clearance rate of ANG II (MCRangii). We have evaluated the MCRangii and the arterial plasma concentrations of ANG II during constant infusions of 1.15 micrograms ANG II/min into chronically instrumented pregnant (n = 6) and nonpregnant (n = 9) sheep. Although the pressor responses were significantly less in the pregnant than in the nonpregnant sheep (17.5 +/- 0.5 vs. 34.9 +/- 3.2 mmHg, P less than 0.001), the values for MCRangii were not different: 56.2 +/- 6.3 ml X min-1 X kg-1 in nonpregnant and 55.9 +/- 4.3 ml X min-1 X kg-1 in pregnant sheep. The steady-state plasma ANG II concentrations during the infusions were slightly less in pregnant than in nonpregnant sheep (388 +/- 36 vs. 454 +/- 36 pg/ml); however, this difference would be responsible for only a 2-mmHg reduction in the pressor response. We conclude that the reduced pressor response to infused ANG II in pregnancy is not due to an increase in MCRangii nor to lower plasma ANG II concentrations.

Cardiovascular effects and clearance of arginine vasopressin in the fetal lamb.

Increased fetal secretion of arginine vasopressin (AVP) occurs in association with complicated pregnancies, asphyxia, and meconium-stained amniotic fluid (AF); yet, the role of AVP in fetal homeostasis remains unclear. Using chronically instrumented, near-term lamb fetuses (n = 8), we have ascertained the cardiovascular responses to doses of AVP ranging from 1.94 to 8.73 mU/min, the clearance of AVP from plasma, and the occurrence of meconium release into AF during AVP infusions. AVP administration resulted in a dose-related rise in arterial pressure; although heart rate fell, the decline was not dose-related and occurred before the pressor response. Clearance of plasma AVP was 60 +/- 8.7 ml X kg-1 X min-1, and the half-time in plasma was 2.8 min. AVP was not cleared across the fetal placenta nor by fetal-maternal transport. However, the AF concentration of AVP rose fourfold after the infusion of AVP was stopped. Meconium release into AF occurred in fetuses infused with AVP at rates greater than or equal to 7.76 mU/min. AVP has hemodynamic effects that mimic fetal responses to intrauterine "stress" and may be causally associated with the fetal release of meconium into AF. Furthermore, plasma AVP is cleared in part by the fetal kidney.

Mechanism of arginine vasopressin release in the sheep fetus.

Maternal and fetal plasma concentrations of arginine vasopressin (AVP) during asphyxial and hypoxemic episodes were ascertained between 130 and 140 days of gestation in chronically catheterized sheep. During an acute asphyxial stress, i.e., decreased PaO2 and pHa and increased PaCO2, maternal AVP in plasma was unaltered, whereas fetal arterial plasma concentrations rose from 1.6-2.2 microunits/ml to 34-385 microunits/ml and were associated with massive expulsion of meconium into the amniotic fluid. Mild hypoxemia, induced while the mother breathed a gas mixture consisting of 85% nitrogen and 15% oxygen, did not affect either maternal or fetal plasma AVP concentrations. The use of 10% inspired oxygen resulted in 60% and 50% reductions in maternal and fetal PaO2, respectively (P less than 0.05). In this instance, the maternal plasma AVP levels were unchanged, whereas the fetal plasma AVP concentration rose from a mean of 2.61 +/- 0.14 (SE) to 10.2 +/- 2.59 microunits/ml (P less than 0.025) within 30 min. Expulsion of meconium into the amniotic fluid did not occur. No evidence or either fetal-maternal placental transfer or fetal-placental clearance of plasma AVP was obtained. Although hypoxemic stress resulted in an elevation of fetal plasma AVP concentration, it does not appear to be the sole factor responsible for AVP release during intrauterine stress. It is suggested that substantial elevations in fetal plasma AVP concentrations may play in integral role in the fetal expulsion of meconium into the amniotic fluid.

Effect of volume expansion on pressor response to angiotensin II in pregnant ewes.

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.

Fetal responses to maternal infusions of angiotensin II.

It is unclear whether the fetus is affected by maternal infusions of angiotensin II; therefore we studied maternal and fetal responses (n = 9) to angiotensin II (1.15, 2.29, 11.5 micrograms/min) infused 5 minutes into the vena cava of chronically instrumented sheep (129 to 137 days of gestation) while monitoring PO2, PCO2, pH, heart rate, uterine blood flow, and arterial and umbilical venous pressures. Pregnant sheep demonstrated expected dose-related increases in mean arterial pressure and decreases in uterine blood flow (p less than 0.05). Increases in fetal mean arterial pressure also correlated with the maternal dose of angiotensin II (r = 0.77, p less than 0.001). Fetal heart rate appeared to increase with 2.29 micrograms/min; however, bradycardia was observed with 11.5 micrograms/min (p less than 0.05) and was associated with decreased PaO2, 19.0 +/- 1.0 to 14.3 +/- 1.4 mm Hg (p less than 0.05), increased PaO2 (p less than 0.05), and decreased umbilical venous PO2, 31.4 +/- 2.3 to 27.0 +/- 1.9 mm Hg. The decreases in PO2 correlated with decreases in uterine blood flow (r = 0.60, p less than 0.002, and r = 0.75, p less than 0.005, respectively). Nevertheless, changes in fetal mean arterial pressure also occurred in the absence of altered fetal oxygenation; thus decreased uterine blood flow and fetal oxygenation alone cannot explain the fetal cardiovascular responses. It is suggested that angiotensin II or an active metabolite may cross the ovine placenta.

Hemodynamic effects of indomethacin in chronically instrumented pregnant sheep.

Indomethacin administration has produced decreases in uteroplacental blood flow in several animal studies; therefore, it has been suggested that the maintenance of uterine blood flow is critically dependent on the continued synthesis of vasodilating prostaglandins. However, vasoconstriction following indomethacin administration may be due to mechanisms other than reduced prostaglandin synthesis. We administered indomethacin (2, 5, or 10 mg/kg) intravenously to seven unanesthetized sheep in late pregnancy and determined the time courses of the uteroplacental and systemic hemodynamic responses, comparing these to the concurrent changes in circulating prostaglandins. Indomethacin administration resulted in rapid increases in systemic and uteroplacental vascular resistance (80% to 100%) and mean arterial pressure (approximately 30%) and in decreases in systemic (approximately 30%) and uteroplacental (0% to 30%) blood flows within 5 minutes. Vasoconstriction was transient, however, and after 60 minutes there was no evidence of uterine or systemic vasoconstriction, although systemic and uterine plasma prostaglandin levels remained reduced for 180 minutes. Thus substantial inhibition of prostaglandin synthesis existed without evidence of concurrent systemic or uteroplacental vasoconstriction, suggesting that uterine blood flow is not directly dependent on maintained prostaglandin synthesis in unstressed pregnant sheep. Furthermore, the transient indomethacin-induced vasoconstriction may not be due to inhibition of prostaglandin synthesis.