Raymond P. Naden

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.

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.

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.

Mechanism of arginine vasopressin release in the sheep fetus.

Summary: 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 μ/ml to 34–385 μ/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 < 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 μ/ml (P < 0.025) within 30 min. Expulsion of meconium into the amniotic fluid did not occur. No evidence of 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 an integral role in the fetal expulsion of meconium into the amniotic fluid.Speculation: Elevations in fetal plasma concentrations of arginine vasopressin are reflective of intrauterine stress and may be representative of an adaptive mechanism whereby the fetus responds to hypoxemia and asphyxia. Measurement of fetal plasma arginine vasopressin, i.e., cord plasma levels, may serve as an indicator of the degree or severity of intrauterine stress. Moreover, increases in arginine vasopressin during fetal asphyxia could be important in the fetal expulsion of meconium into the amniotic sac, thereby establishing the situation necessary for meconium aspiration.

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.

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.

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.

305 CARDIOVASCULAR EFFECTS AND CLEARANCE OF EXO-GENOUS ARGININE VASOPRESSIN (AVP) IN THE FETAL LAMB

The concentration of AVP has been shown by us to be elevated in the human and lamb fetus during perinatal stress, especially hypoxia and asphyxia, with levels being greatest in association with meconium in the amniotic fluid (AF). The role of AVP in these instances is unclear; thus, we studied in fetal lambs the cardiovascular effects and clearance of infused AVP. AVP was infused into the vena cava of fetal lambs, 129-137 days gestation, at doses of 1.94, 3.88, and 7.76 mU/min for 75 min (n=5) while monitoring fetal and maternal mean arterial pressure (MAP), heart rate (HR), and umbilical and uterine blood flows. Samples were obtained for serial determinations of fetal plasma and AF AVP in 3 studies. Fetal plasma AVP rose from 2.0 ± .02 μU/ml (Mean ± SE) to 12 to 67 μU/ml at 60 min without changes in arterial blood gases. AF AVP increased at 60 and 120 min post-infusion, but did not correlate with plasma levels. Fetal MAP at 60 min rose 16 to 24%* while HR fell 9 to 43%*; both responses were dose dependent. Umbilical and uterine blood flows and maternal MAP and HR did not change. Of note, meconium stained AF occurred in association with intermediate and high rates of AVP infusions. The T1/2 of AVP in fetal plasma was 14 ± 2.5 min and the clearance was 51 ± 10 ml/min.kg. We conclude that AVP 1) causes a rise in MAP and fall in HR that relates to circulating levels of AVP, suggesting AVP may mediate these changes during episodes of fetal stress, and 2) may be responsible for the expulsion of meconium into the AF during such episodes. *p < .01