Effect of endothelin-1 on the uterine vasculature of the pregnant and estrogen-treated nonpregnant sheep.

OBJECTIVE: This study was designed to evaluate the uterine vascular responses to endothelin-1 in pregnant and estrogen-treated nonpregnant sheep. STUDY DESIGN: Seven pregnant and five nonpregnant oophorectomized ewes received local uterine artery infusions of endothelin-1, norepinephrine, and phenylephrine. Arterial blood pressure, heart rate, and uterine blood flow were recorded. RESULTS: Endothelin-1 (0.01 to 3.0 micrograms/min), norepinephrine (0.1 to 3 micrograms/min), and phenylephrine (0.1 to 10 micrograms) produced significant dose-related decreases in uterine blood flow and increases in uterine vascular resistance. On a nanomoles infused per minute basis, endothelin-1 was much more potent than norepinephrine and phenylephrine as a uterine artery vasoconstrictor in both pregnant and nonpregnant sheep. The uterine vascular responses to norepinephrine and phenylephrine were similar in pregnant and nonpregnant ewes, whereas response to endothelin-1 was blunted in pregnancy. CONCLUSION: Endothelin-1 is an extremely potent uterine vasoconstrictor in both pregnant and nonpregnant ewes, but the uterine vascular responsiveness to endothelin-1 is decreased in pregnancy.     

Placental vascular responses to nicardipine in the hypertensive ewe

Calcium channel blockers are arterial vasodilators effective in the treatment of hypertension. Therefore nicardipine, a dihydropyridine calcium channel blocker, should modulate angiotensin II-induced vasoconstriction. Regional blood flows were measured with radioactive microspheres in five chronically catheterized near-term ewes both before and 15 minutes after maternal infusion of angiotensin II at 5 micrograms/min. Nicardipine was then administered intravenously at 20 micrograms/kg/min over 2 minutes while the angiotensin II infusion was maintained. Blood flows were measured after 5 minutes. Maternal blood pressure levels were increased by angiotensin II from 83 +/- 4 mm Hg to 114 +/- 5 mm Hg, and were decreased to 70 +/- 4 mm Hg by nicardipine (p less than 0.05). Nicardipine also reversed angiotensin II-induced vasoconstriction in the renal and endomyometrial vascular beds (p less than 0.05). Unexpectedly, however, nicardipine worsened placental vasoconstriction caused by angiotensin II, as placental blood flow fell from 242 +/- 32 ml.min-1.kg-1 fetal weight to 128 +/- 7 ml.min-1.kg-1 fetal weight (p less than 0.05), and placental resistance increased from 0.48 +/- 0.04 mm Hg.ml-1.min.kg-1 fetal weight to 0.55 +/- 0.05 mm Hg.ml-1.min.kg-1 fetal weight (p less than 0.05). Nicardipine reverses angiotensin II-induced vasoconstriction systemically and in the kidney and uterus of the pregnant ewe, but does not reverse placental vasoconstriction and may significantly alter fetal cardiorespiratory status.     

Effect of alpha 1 receptor blockade upon maternal and fetal cardiovascular responses to cocaine

Previous studies in pregnant ewes have demonstrated that intravenous (IV) cocaine produces increased maternal blood pressure and vasoconstriction of the uterine arteries, resulting in decreased uterine blood flow and decreased fetal oxygen levels. To determine whether these responses to cocaine were mediated by alpha 1-adrenergic receptor stimulation, cocaine was administered to four pregnant ewes before and after phenoxybenzamine hydrochloride, an alpha 1 receptor antagonist. Before phenoxybenzamine infusion, cocaine 2.0 mg/kg produced a 53% increase in maternal mean arterial pressure (MAP), a 50% reduction in total uterine blood flow, and a 191% increase in uterine vascular resistance. Cocaine also increased fetal MAP by 24%, increased the fetal heart rate (FHR) by 51%, and reduced fetal PO2 by 29%. Alpha 1 receptor blockade after phenoxybenzamine 5.0 mg/kg was confirmed by a lack of change in uterine blood flow to IV norepinephrine 30 micrograms before cocaine administration. After phenoxybenzamine, cocaine produced no increase in maternal or fetal MAP. However, total uterine blood flow decreased 44%, uterine vascular resistance increased 59%, FHR increased 36%, and fetal PO2 fell 18%. Because the fetal responses mimicked the maternal responses to cocaine both before and after phenoxybenzamine, phenoxybenzamine apparently crossed the placenta to block fetal alpha 1 receptors as well. Alpha 1-adrenergic receptor stimulation is the major mechanism for the maternal and fetal hypertensive responses to cocaine. Although cocaine produces uterine artery vasoconstriction primarily by alpha 1 adrenergic receptor stimulation, its vasoconstrictive effects may involve other vasoactive neurotransmitters, such as dopamine or serotonin.     

Ovine fetal cardiorespiratory response to nicardipine

Nicardipine, a calcium antagonist associated with decreased uterine blood flow in near-term pregnant rabbits and fetal asphyxia after maternal administration in the rhesus monkey and sheep, was infused directly to the fetus in six chronically prepared pregnant ewes at 128 days' gestation. Changes in fetal mean arterial and diastolic blood pressure levels at 2 and 30 minutes after bolus injection of 50 micrograms were minimal; by 60 minutes these values had returned to preinfusion levels. No significant changes were observed after infusion of 100 micrograms of nicardipine. Fetal heart rate, fetal arterial blood gas values, and maternal cardiovascular variables did not change at either dose. Fetal plasma concentrations of nicardipine were 78 +/- 28 ng/ml and 114 +/- 48 ng/ml at 30 minutes after infusion of 50 micrograms and 100 micrograms, respectively, well within the range previously reported to be associated with fetal asphyxia. These data suggest that the previously reported fetal acidosis from maternal infusion of nicardipine may be primarily due to a decrease in maternal uterine blood flow rather than a direct fetal effect of the drug.     

Differential effects of intravenous hydralazine on myoendometrial and placental blood flow in hypertensive pregnant ewes.

OBJECTIVE: The differential vasoactive effects of hydralazine on the uteroplacental vascular bed were studied. STUDY DESIGN: After control measurements were taken, near-term chronically prepared pregnant sheep were continuously infused with angiotensin II. Maternal arterial pressure was increased by 32 mm Hg. Hydralazine was then administered; the effects on regional resistance and blood flow were evaluated with a radionuclide-labeled microsphere technique. Analysis of variance for repeated measures was used to compare observations. RESULTS: When compared with the hypertensive state, hydralazine caused the following changes by 40 minutes (mean +/- SEM): Although maternal blood pressure fell 31% +/- 5% (p = 0.0005), placental blood flow was unchanged, total uteroplacental blood flow increased 24% +/- 8% (p = 0.03), total uteroplacental resistance decreased 43% +/- 4% (p = 0.0002), placental resistance decreased 19% +/- 9% (p = 0.01), myoendometrial blood flow increased 390% +/- 82% (p = 0.0005), and myoendometrial resistance decreased 82% +/- 4% (p = 0.0005). CONCLUSIONS: In angiotensin II-induced hypertensive ewes, hydralazine is an effective dilator of the uteroplacental vascular bed and can maintain placental blood flow while blood pressure.     

Effects of dexamethasone on the uterine and umbilical vascular beds during basal and hypoxemic conditions in sheep

OBJECTIVE: The purpose of the study was to test the hypotheses that maternal treatment with dexamethasone leads to a reduction in basal umbilical blood flow and diminishes the fetal umbilical hemodynamic response to acute hypoxemic stress in sheep. STUDY DESIGN: While under general anesthesia, 23 ewes and their fetuses were instrumented with vascular catheters and transonic blood flow probes around a uterine and umbilical artery at 117 days of gestation (term, approximately 145 days). At 124 days, the ewes were injected intramuscularly with 2 doses of either dexamethasone (12 mg) or saline solution at 24-hour intervals. All animals experienced 2 episodes of hypoxemia during treatment (125+/-1 days) and after treatment (128+/-1 days). RESULTS: Maternal dexamethasone treatment caused a sustained increase in fetal arterial blood pressure (from 41+/-3 mm Hg to 45+/-3 mm Hg) and a transient fall in umbilical vascular conductance (from 6.2+/-0.9 mL. min(-1). [mm Hg](-1) to 5.4+/-0.7 mL. min(-1). [mm Hg](-1)). During both episodes of hypoxemia, there was a significant increase in umbilical blood flow in the controls, but not in the dexamethasone-treated animals. CONCLUSION: Maternal dexamethasone treatment with doses used in human clinical practice significantly decreased basal umbilical vascular conductance and prevented the normal increase in umbilical blood flow that is induced by acute hypoxemia in fetal sheep.     

Dose-response curves of the uterine and placental vascular beds to prostaglandin I2

Local infusion of prostaglandin I2 (PGI2) has been reported to dilate the uteroplacental vasculature in a dose-dependent manner. In this experiment we attempted to distinguish the placental and nonplacental (uterine) components of this response over four concentrations of PGI2. Eleven near-term sheep were chronically instrumented for determination of regional blood flows by the use of radioactive microspheres. PGI2 was administered in a retrograde manner via a branch of the middle uterine artery at 1, 3, 10, and 20 micrograms/min. Flows were measured before (control) and after 5-minute infusions at each of the four concentrations (test). The uterine vasculature vasodilated in response to local PGI2 infusion. The 10 micrograms/min dose, for example, produced a mean (+/- SEM) flow of 0.70 +/- 0.07 ml/min/gm; the control value was 0.41 +/- 0.03 ml/min/gm (p less than 0.001). At 20 micrograms/min the test and control flows were 0.75 +/- 0.16 and 0.36 +/- 0.06 ml/min/gm (p less than 0.05), respectively. Uterine vascular resistance fell in a dose-dependent manner as well. There was no evidence of placental vasodilation at any of the doses tested. Renal vasodilation and decreased systemic arterial pressure at higher PGI2 doses suggest a recirculation effect. We conclude that PGI2 does not dilate the placental vasculature over the dose range of 1 to 20 micrograms/min and that the reported vasodilation of the uteroplacental vasculature is a result of decreased resistance in the uterine vasculature alone.     

Cardiac and uterine hemodynamic responses to ritodrine hydrochloride administration in pregnant sheep.

The changes in the maternal circulation following administration of ritodrine hydrochloride were investigated in chronically prepared pregnant sheep. Low infusion rates of ritodrine (see text) elevated the maternal heart rate and cardiac output and decreased peripheral vascular resistance. Stroke work fell while minute work increased. The distribution of uterine blood flow did not change, as measured with microspheres. Simultaneously measured fetal cardiac output and umbilical blood flow were not altered. When ritodrine infusion rates (see text) were increased there was a slight but significant decrease in uterine perfusion pressure, and an increase in uterine vascular resistance with uterine blood flow decreasing. These changes were observed when the ewes were not in labor, and similar changes were again recovered with ewes in labor despite the simultaneous inhibition of uterine contractions. Selective beta blockade with practolol during ritodrine administration decreased the maternal tachycardia without affecting cardiac output, peripheral vascular resistance, or uterine vascular resistance.     

Systemic and uterine responses to alpha-adrenergic stimulation in pregnant and nonpregnant ewes

Attenuated systemic pressor responses to infused angiotensin II characterize normal human and ovine pregnancy; moreover, uterine vascular refractoriness is greater than that of the systemic vasculature overall. It remains unclear whether this generalized refractoriness also pertains to other vasoconstrictors; therefore we studied simultaneous systemic and uterine responses to alpha-agonists in pregnant (n = 6) and nonpregnant (n = 6) sheep. Mean arterial pressure, heart rate, uterine blood flow, and cardiac output were measured before and during infusions of norepinephrine (0.456 to 45.84 micrograms/min) and phenylephrine (1.29 to 129 micrograms/min). Both alpha-agonists caused dose-dependent increases (p less than 0.01) in mean arterial pressure and systemic vascular resistance and decreases in cardiac output (p less than 0.01) in nonpregnant and pregnant animals; however, nonpregnant pressor responses exceeded pregnant ones. Nonpregnant ewes also had greater decreases in uterine blood flow (p less than 0.05) and increases in uterine vascular resistance (p less than 0.05); furthermore, increases in uterine vascular resistance exceeded those of systemic vascular resistance in both groups (p less than 0.01). Attenuated uterine and systemic responses to alpha-agonists characterize normal ovine pregnancy; however, in contrast to the results with angiotensin II, the uterine vascular bed is substantially more responsive to alpha-agonists than the systemic vasculature overall.     

Intravenous clonidine hydrochloride toxicity in pregnant ewes

Administration of intravenous clonidine hydrochloride has been advocated to rapidly control blood pressure in severe preeclampsia. To examine clonidine's acute maternal and fetal effects were intravenously injected 300 micrograms clonidine in eight chronically prepared normotensive near term ewes. Unlike intravenous saline solution injection, clonidine produced significant toxicity--intraamniotic pressure increased 97 +/- 27% (p less than 0.05), uterine blood flow decreased 55 +/- 7% (p less than 0.001), maternal and fetal serum glucose increased 158 +/- 23% and 249 +/- 91%, respectively (p less than 0.001), and maternal and fetal Po2 decreased to 44 mm Hg +/- 4 mm Hg and 13 mm Hg +/- 1 mm Hg, respectively (p less than 0.05). Maternal and fetal blood pressure and serum cortisol were unaffected by clonidine, whereas heart rate decreased. No adverse maternal or fetal effects were noted with serum clonidine concentrations less than 1.0 ng/ml. Direct fetal infusion of clonidine did not lower fetal arterial Po2 levels, although heart rates decreased and serum glucose levels increased. The multiple effects of clonidine infusion are best explained by actions on alpha 2-adrenergic receptors. These results suggest that intravenous administration of clonidine may adversely affect the fetus by direct actions and by alterations in maternal physiology.     

Fetal hemodynamic response to maternal intravenous nicotine administration.

OBJECTIVES: Our study was designed to test the hypothesis that maternally administered nicotine has significant effects on fetal hemodynamics and umbilical systolic/diastolic ratios. STUDY DESIGN: Nine pregnant ewes received maternal intravenous infusions of 10, 20, and 30 micrograms/kg/min of nicotine. Maternal and fetal blood pressure, heart rate, and uterine and umbilical blood flow were recorded. RESULTS: Maternal intravenous administration of nicotine (10, 20, and 30 micrograms/kg/min of maternal body weight) produced significant (p < 0.05) increases in fetal blood pressure (2%, 11%, and 25%, respectively), decreases in fetal heart rate (0%, 8%, and 12%), and decreases in umbilical blood flow (0%, 0%, and 19%). Umbilical systolic/diastolic ratios increased slightly at the 30 micrograms/kg/min dose of nicotine, but these changes did not reach significance. Maternal blood pressure increased (10%, 25%, and 53%), and uterine vascular resistance increased (5%, 64%, and 344%) significantly (p < 0.05); uterine blood flow increased at the 10 micrograms/kg/min dose (+5%) and decreased by 23% and 42% at the highest two doses of nicotine. CONCLUSION: Maternal nicotine administration in late-term pregnant sheep produced significant increases in fetal arterial blood pressure and umbilical vascular resistance, decreased fetal heart rate, and umbilical blood flow but did not significantly alter systolic/diastolic ratios.     

A comparative study of vascular responsiveness of myometrial and omental small resistance arteries in late-gestation sheep.

OBJECTIVE: We determined whether local regulation by vasoactive agents differs in the myometrial and omental vascular beds in the pregnant sheep. Specifically, we hypothesized that there would be blunting of in vitro responses to constrictor agonists, enhancement of sensitivity to dilator agonists, or both in myometrial compared with omental resistance arteries. STUDY DESIGN: We compared in vitro responsiveness of small resistance intramyometrial and omental arteries from near-term pregnant ewes to the vasoconstrictor agents norepinephrine, U46619 (a thromboxane sympathomimetic), and potassium and the vasodilator agents acetylcholine and bradykinin. RESULTS: The vascular sensitivity and the maximum response of intramyometrial small arteries to U46619 was attenuated compared with that of omental arteries. There were no significant differences between the intramyometrial and omental arteries in response to norepinephrine, potassium, acetylcholine, or bradykinin. CONCLUSIONS: These results support regional heterogeneity of regulation of function in different maternal vascular beds during pregnancy. The relative insensitivity of the myometrial arteries to the thromboxane mimetic indicates the existence of decreased constrictor function that may facilitate preservation of uterine blood flow in vivo.     

The effect of a leukotriene receptor antagonist, FPL 55712, on estrogen-induced uterine hyperemia in the nonpregnant rabbit

Estrogen results in delayed uterine hyperemia. We postulate that the leukotrienes may be the mediators of the uterine vascular responses to estrogen. To test this hypothesis, we gave FPL 55712, a selective leukotriene antagonist, to estrogen-primed, nonpregnant rabbits and measured regional blood flows by the radioactive microsphere technique. In 10 chronically catheterized animals, blood flows were measured in the control condition (C), and again 2 hours after systemic administration of estradiol (EST). Thirty minutes before administration of estradiol, five animals received systemic FPL 55712, whereas five animals received vehicle only. The vehicle group showed the expected increase in uterine blood flow from 0.62 +/- 0.1 to 2.72 +/- 0.4 ml X min-1 X gm-1, and decrease in uterine resistance from 144 +/- 31 to 34 +/- 8 peripheral resistance units (PRU) X gm, with a resistance ratio (estradiol/C) of 0.23 +/- 0.01. Unexpectedly, the FPL 55712 group showed a further increase in uterine blood flow from 0.66 +/- 0.1 to 4.60 +/- 0.3 ml X min-1 X gm-1, and a decrease in resistance from 133 +/- 25 to 17 +/- 1 PRU X gm, with a resistance ratio of 0.13 +/- 0.02. The leukotriene antagonist FPL 55712 potentiates estrogen-induced uterine hyperemia by 77% (P less than 0.001). These data suggest that leukotrienes do not mediate, but rather inhibit, the uterine vascular responses to estrogen.     

Effect of fetal and maternal intravascular antipyrine infusion on maternal plasma prostaglandin concentrations in the pregnant sheep at 104 to 127 days' gestation

Antipyrine is commonly used to measure umbilical and uterine blood flow in the pregnant sheep. In the present experiment we investigated the effect of antipyrine on prostaglandin metabolism. Four pregnant ewes at 104 to 127 days' gestation were infused with either 1, 4, or 15 mg of antipyrine per minute via the fetal jugular vein. The 15 mg X min-1 dose was also infused into the maternal jugular vein in a fourth experiment. Prostaglandins in the uterine vein draining the pregnant horn were measured by radioimmunoassay and antipyrine by high-performance liquid chromatography. No change in the concentrations of either 13,14-dihydro-15-keto-prostaglandin F2 alpha or 6-keto-prostaglandin F1 alpha was observed with infusion of antipyrine at 1 mg X min-1. The 4 and 15 mg X min-1 infusion rates into the fetal jugular vein induced a significant decrease (p less than 0.05) in maternal uterine vein 13,14-dihydro-15-keto-prostaglandin F2 alpha plasma concentrations. These concentrations decreased from 669.3 +/- 161.3 pg X ml-1 (mean +/- SD) before infusion to 306.5 +/- 104.0 pg X ml-1 after 3 hours of infusion at 4 mg X min-1 and from 744.2 +/- 256.8 to 105.0 +/- 24.2 pg X ml-1 at 15 mg X min-1. Significant changes in maternal uterine vein plasma 6-keto-prostaglandin F1 alpha and the 6-keto-prostaglandin F1 alpha/13,14-dihydro-15-keto-prostaglandin F1 alpha ratio occurred only at the 15 mg X min-1 infusion of antipyrine into the fetal jugular vein (p less than 0.05). Maternal uterine vein 6-keto-prostaglandin F1 alpha fell from 86.0 +/- 31.6 to 37.0 +/- 11.5 pg X ml-1 and the 6-keto-prostaglandin F1 alpha/13,14-dihydro-15-keto-prostaglandin F2 alpha ratio rose from 0.14 +/- 0.10 to 0.35 +/- 0.10. We conclude that: antipyrine at doses currently used to measure uterine and umbilical blood flows inhibits 13,14-dihydro-15-keto-prostaglandin F2 alpha production and infusion rates of antipyrine less than 1 mg X min-1 probably do not affect maternal prostaglandin metabolism. We therefore recommend that if this method is to be used for measuring blood flow, antipyrine infusion rates should be less than 1 mg X min-1.     

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.     

Fetal and maternal endocrine responses to prolonged reductions in uterine blood flow in pregnant sheep

To examine the effects of sustained (48-hour) hypoxemia on fetal and maternal adrenocorticotropic hormone concentrations and on maternal progesterone, uterine blood flow was reduced in eight sheep at day 128 of pregnancy by means of an adjustable Teflon clamp placed around the maternal common internal iliac artery. Control measurements were made in four animals in which the vascular clamp was not adjusted. Fetal PaO2 fell from 20.6 +/- 1.1 mm Hg (mean +/- SEM) to 16.6 +/- 0.6 mm Hg within 1 hour after application of the clamp and remained suppressed during 48 hours. There was a transient acidemia at 1 to 2 hours that had corrected by 8 hours. Fetal adrenocorticotropic hormone levels rose from 24 +/- 6 to 1320 +/- 205 pg/ml at 2 hours but decreased by 16 hours. Measured by high-pressure liquid chromatography, more than 95% of immunoreactivity corresponded to adrenocorticotropic hormone1-39. Fetal cortisol levels rose by 6 hours and remained elevated through 48 hours. Maternal adrenocorticotropic hormone, cortisol, and progesterone levels were unchanged during the study period. We conclude that fetal hypoxemia-acidemia after restriction of uterine blood flow provokes fetal adrenocorticotropic hormone release, but the elevation in adrenocorticotropic hormone is not sustained. However, the level of fetal cortisol rises progressively, consistent with fetal adrenal activation.     

Circulatory responses to prolonged hypoxemia in fetal sheep

Experiments were conducted in 11 chronically catheterized pregnant sheep to determine the distribution of blood flow within the fetus during prolonged (48 hours) hypoxemia secondary to the restriction of uterine blood flow. Uterine blood flow was mechanically restricted with a polytetrafluoroethylene vascular clamp placed around the maternal common internal iliac artery such that mean (+/- SEM) fetal arterial oxygen tension decreased from 23.4 +/- 1.9 to 17.3 +/- 0.8 mm Hg at 1 hour of hypoxemia and remained low for 48 hours. There was an initial increase in fetal arterial carbon dioxide pressure from 48.5 +/- 0.9 mm Hg during the control period to 56.2 +/- 2.3 mm Hg at 1 hour; this parameter subsequently returned to control values, whereas base excess showed a transient decrease. Fetal cerebral, myocardial, and adrenal blood flows were significantly increased at 1, 24, and 48 hours of hypoxemia. In contrast, there was no change in nuchal muscle or renal blood flows with hypoxemia of this magnitude. Cotyledonary blood flow increased transiently by 38% at 1 hour of hypoxemia, but was not changed from control at 24 and 48 hours. These experiments demonstrate that the sheep fetus is able to maintain the normal protective circulatory adjustments seen with acute hypoxemia for up to 48 hours in the absence of progressive metabolic acidemia.     

Effect of calcitonin gene-related peptide on the uterine vasculature of the nonpregnant ewe.

OBJECTIVES: The current study was designed to evaluate the uterine vascular effects of calcitonin gene-related peptide on the uterine vasculature of nonpregnant sheep and compare them with the effects of prostacyclin. STUDY DESIGN: Five nonpregnant oophorectomized ewes were instrumented with uterine and pulmonary artery flow probes and catheters. Dose-response curves were constructed according to increasing doses of calcitonin gene-related peptide (0.01, 0.03, 0.1, 0.3, 1, and 3, micrograms/min) and prostacyclin (0.03, 0.1, 0.3, 1, 3, and 10 micrograms/min) via 10-minute uterine artery infusions. RESULTS: Both calcitonin gene-related peptide and prostacyclin produced a significant increase in uterine blood flow and a decrease in uterine vascular resistance. Calcitonin gene-related peptide was found to be approximately 17 times more potent than prostacyclin as a vasodilator. Local uterine artery infusions of calcitonin gene-related peptide led to significant increases in heart rate but did not alter blood pressure, cardiac output, or total peripheral resistance at the doses tested. In contrast, at doses of prostacyclin that produced similar uterine vasodilatation, prostacyclin led to significant decreases in systemic arterial blood pressure and total peripheral resistance and increases in heart rate and cardiac output. CONCLUSION: These data strongly suggest that calcitonin gene-related peptide, an endogenously occurring vasoactive peptide, could play an important role in regulating uterine and systemic hemodynamics.     

Effect of Ro 61-1790, a selective endothelin-A receptor antagonist, on systemic and uterine hemodynamics and fetal oxygenation in sheep.

OBJECTIVE: Endothelin-1 is reportedly elevated in preeclampsia, and studies in our laboratory have shown that infusion of endothelin-1 produces increased mean arterial pressure, hemoconcentration, and proteinuria, while decreasing uterine blood flow. If a role in preeclampsia is confirmed for endothelin-1, therapeutic intervention may involve selective endothelin-A receptor blockers. Thus, this study was designed to determine the effects of Ro 61-1790, a selective endothelin-A receptor inhibitor, on mean arterial pressure, heart rate, and uteroplacental blood flow in pregnant and nonpregnant sheep. STUDY DESIGN: Seven pregnant and seven nonpregnant sheep were instrumented with indwelling femoral artery and vein catheters and bilateral uterine artery flow probes, allowing determination of mean arterial pressure, heart rate, and uteroplacental blood flow. After baseline administration, animals received intravenous Ro 61-1790 either 1 mg/kg or 3 mg/kg, and hemodynamic responses were monitored for 120 minutes. RESULTS: Intravenous administration of Ro 61-1790 at 1 mg/kg had no effect on the parameters measured in either group studied. However, at 3 mg/kg, Ro 61-1790 caused an increase in total uterine blood flow in nonpregnant sheep from 22 +/- 6 mL/min to 51 +/- 15 mL/min. This occurred in the absence of significant changes in mean arterial pressure. In pregnant animals, administration of 3 mg/kg Ro 61-1790 decreased mean (+/- SEM) uteroplacental blood flow by 20% (from 771 +/- 130 mL/min to 621 +/- 110 mL/min) and increased uterine vascular resistance transiently. Administration of Ro 61-1790 had no significant effect on fetal mean arterial pressure, heart rate, or oxygenation. CONCLUSIONS: These data suggest that endogenous endothelin-1 may play an important role in regulating uterine vascular tone in pregnant and nonpregnant sheep and that inhibition of endogenous endothelin-1 may lead to reductions in uteroplacental perfusion in pregnant animals.     

Effects of maternally administered dexamethasone and acute hypoxemia at 0.7 gestation on blood pressure and placental perfusion in sheep.

Glucocorticoid administration to women in premature labor significantly decreases preterm infant morbidity and mortality. Fetal exposure to maternally administered glucocorticoids in late gestation causes fetal hypertension. We determined the effects of a single course (4 injections at 12-hr intervals) of dexamethasone (DM; 2 mg, a weight-adjusted dose equivalent to one-third the dose administered to pregnant women) or saline (S) in sheep at 103-104 days of gestation (dGA; term 149 dGA) on maternal and fetal blood pressure (BP). We also determined the BP and placental perfusion effects of acute maternal hypoxemia. Venous and arterial catheters were placed in 10 ewes and fetuses (DM = 6, S = 4) at 96 +/- 1 dGA. Maternal and fetal placental perfusion was determined with fluorescent microspheres. Dexamethasone increased fetal but not maternal BP; maternal and fetal placental blood flow and vascular resistance (VR) were unchanged. At 105 dGA, hypoxemia was induced for 1 hr by maternal nitrogen gas inhalation to decrease fetal PaO2 by 40%. Hypoxemia increased BP in DM but not S fetuses or mothers in either group. Hypoxemia decreased maternal placental blood flow by 39 +/- 7% and 51 +/- 9% and increased maternal placental VR by 65 +/- 7% and 69 +/- 6% in S and DM mothers, respectively. Hypoxemia did not alter fetal placental blood flow or VR in either treatment group. In summary, at 0.7 gestation, DM induces a hypertensive response to fetal hypoxemia that is characteristic of older fetuses but does not alter hypoxemia-induced reductions in maternal placental blood flow.