Fetal vascular responses to maternal nicardipine administration in the hypertensive ewe

Calcium channel blockers such as nicardipine act as arterial vasodilators and are effective in the treatment of hypertension. Although they are also effective tocolytic agents, fetal effects have not been fully studied. Fifteen chronically catheterized near-term ewes were studied. Maternal and fetal cardiorespiratory parameters were measured in the control period and again 15 minutes after maternal venous infusion of angiotensin II. Nicardipine 20 micrograms/kg/min was given over 2 minutes and maternal and fetal cardiorespiratory parameters and fetal blood flow were measured 5.30 and 60 minutes later. Nicardipine reversed maternal hypertension and produced transient tachycardia. Fetuses responded initially with transient bradycardia and then developed hypercapnia and acidemia (p less than 0.03) by 60 minutes after nicardipine. Fetal placental blood flow decreased and vascular resistance increased by 5 minutes after nicardipine but returned toward control values after 30 minutes. Unexpectedly we observed the death of five fetuses by 65 minutes after nicardipine. We conclude that the administration of nicardipine in the hypertensive ewe results in significant alterations of fetal cardiorespiratory status and placental function that may lead to acidemia.     

Placental vascular responses to 6-keto-prostaglandin E1 in the near-term sheep

6-Keto-prostaglandin E1 (6-keto-PGE1) is a biologically active, stable metabolite of prostaglandin I2 (PGI2). It has vasoactive properties similar to those of PGI2 and it has been shown to decrease the resistance of the renal, mesenteric, and pulmonary vascular beds. PGI2 is synthesized by the pregnant uterus and is vasoactive in the ovine placenta. The effects of 6-keto-PGE1 on uterine and placental blood flow in pregnant ewes were determined for comparison with those of PGI2. Near-term ewes and their fetuses were chronically catheterized to permit the measurement of regional blood flow by the radioactive microsphere method. In six sheep a 5-minute maternal jugular infusion of 3.25 micrograms/kg/min of 6-keto-PGE1 decreased mean arterial blood pressure from 89 +/- 4.8 to 63 +/- 7.1 mm Hg. Uterine vascular resistance decreased from 0.55 +/- 0.11 to 0.35 +/- 0.05 peripheral resistance units (PRU), but maternal cotyledonary resistance increased from 0.19 +/- 0.04 to 0.27 +/- 0.03 PRU. In five sheep a fetal intravenous infusion of 18 micrograms/min of 6-keto-PGE1 decreased mean fetal blood pressure from 43 +/- 2 to 29 +/- 2 mm Hg. Cotyledonary vascular resistance increased from 0.30 +/- 0.02 to 0.55 +/- 0.09 PRU . kg-1. In these sheep there were no significant changes in maternal uterine, renal, or cotyledonary blood flows. These results indicate that 6-keto-PGE1 is similar to PGI2 in that it produces maternal cotyledonary vasoconstriction, hypotension, and vasodilation in other organs.     

Placental vascular morphogenesis

Appropriate growth and development of the placenta is essential for fetal growth and wellbeing, and indeed may be an important factor in determining adult health. As the fetus grows its demands increase and the capacity of the placenta to facilitate transfer between the fetal and maternal circulations increases as gestation progresses. The principal units for diffusional exchange of oxygen are the terminal villi, and these develop in the third trimester. It is thought that capillary growth within the villi drives the growth of these structures which are characterized by a high proportion of their volume being occupied by fetal capillaries and extreme thinning of the trophoblast and endothelial cell layers. In the first trimester the PO2 in the intervillous space is low and rises sharply at the start of the second. Endothelial growth is influenced by a variety of soluble factors, and several of these are regulated by oxygen, for example, vascular endothelial growth factor (VEGF), angiopoietin 2, and soluble flt (a VEGF antagonist). Thus, fetal demand may regulate villous growth and differentiation by altering local PO2 which, in turn, modulates growth factors (or their antagonists) to regulate endothelial growth and vessel re-modelling.     

Placental transfer of the thromboxane synthetase inhibitor ridogrel in the late-pregnant ewe.

OBJECTIVES: To assess the occurrence of placental transfer of the thromboxane synthetase inhibitor ridogrel in the pregnant ewe and to determine its effect on prostanoid levels in the ewe and fetal lamb, on uterine contractility and on maternal and fetal hemodynamics. STUDY DESIGN: Five chronically instrumented pregnant ewes at 122 days of gestation received intravenous infusions of 5 mg/kg/3 h ridogrel and solvent. Maternal and fetal arterial samples were obtained at predetermined intervals to determine concentrations of ridogrel and prostaglandin metabolites TXB2, 6-keto-PGF1alpha, PGF2alpha, and PGE2. Maternal and fetal responses of blood flow and pressures were determined. RESULTS: Fetal ridogrel levels were 25% of maternal concentrations. Ridogrel showed rapid and marked thromboxane synthetase inhibition and augmentation of levels of prostaglandin metabolites. There was no evidence of change in amniotic pressure, uterine blood flow, maternal and fetal blood pressure and heart rate. CONCLUSION: Ridogrel is a potent thromboxane synthetase inhibitor which passes the sheep placenta, does not influence maternal and fetal hemodynamics and uterine contractility, and shows similar antiplatelet activity in the ewe and the fetal lamb.     

Placental bed spiral arteries in the hypertensive disorders of pregnancy

OBJECTIVE--The investigation of the histology of the placental bed spiral arteries in normal pregnancy and in pregnancies complicated by hypertension, with or without proteinura. DESIGN--An observational study, based on women having caesarean sections for clinical reasons. SUBJECTS--17 normal pregnant women, 43 with gestational hypertension, of whom 39 had proteinuria, 17 with chronic hypertension, of whom 6 had proteinuria, and 5 with unclassified hypertension. INTERVENTIONS--Placental bed biopsies obtained during caesarean section. MAIN OUTCOME MEASURES--Histological appearance of sections stained with haematoxylin and eosin PAS and Lendrum's MSB. RESULTS--Biopsies containing spiral arteries were obtained from 6 normotensive and 44 hypertensive women. Trophoblastic invasion was present in 5 of the 6 normotensive biopsies but absent in the majority of those with hypertension. Subintimal proliferation was seen in all the normotensive biopsies but in only 8 of 28 from those with gestational hypertension and proteinuria. Other features seen predominantly or only in the hypertensive biopsies, in order of frequency, were medial hyperplasia, fibrin deposits, acute atherosis, endothelial vacuolation and thrombosis. CONCLUSION--Absence of physiological changes may not be peculiar to preeclampsia but may be associated or even a result of various forms of hypertension in pregnancy. Spiral arteries show a spectrum of changes in hypertensive pregnancies that do not appear to bear a clear-cut relation to the clinical signs.     

Review of fetal cardiovascular and metabolic responses to diabetic insults in the pregnant ewe

Studies with pregnant sheep are reviewed, which were designed to investigate whether short-term episodes of maternal hyperglycemia or hyperketonemia were detrimental to the fetus, whether ketones can cross the ovine placenta, and whether the combination of maternal hyperglycemia and hyperketonemia would contribute to an increased risk of fetal morbidity. It is concluded that acute increases in maternal ketones appear to be more detrimental to the fetus than acute increases in maternal glucose, as assessed by fetal cardiovascular, metabolic, and blood gas changes.     

Fetal vascular responses to prostacyclin

Prostacyclin is a potent vasodilator produced by both maternal and fetal tissues that dilates the umbilical placental vasculature in vitro. To test the hypothesis that prostacyclin dilates the fetal placental circulation in vivo, we measured blood flow by the radioactive microsphere technique in six unanesthetized near-term ovine fetuses before and during prostacyclin infusion. Fetal mean arterial pressure fell 15% from 35 +/- 3 to 31 +/- 3 mm Hg (p less than 0.05) during prostacyclin infusion, and heart rate increased from 182 +/- 6 to 208 +/- 19 beats/min (p less than 0.05). Placental blood flow changed from 240 +/- 58 to 191 +/- 46 ml.min-1.kg-1 fetal weight (p = 0.07), whereas vascular resistance was unchanged (0.16 +/- 0.04 to 0.18 +/- 0.06 mm Hg.ml-1.min.kg fetal weight). Fetal arterial pH decreased from 7.33 +/- 0.03 to 7.28 +/- 0.02 (p less than 0.05) during prostacyclin infusion, with a significant decrease in base excess from -1.2 +/- 1.4 to -3.1 +/- 1.6 (p less than 0.05) and a trend toward hypercarbia (p = 0.07). We conclude that in vivo administration of prostacyclin to the ovine fetus does not cause fetal placental vasodilation and does cause a significant fetal acidemia. The mechanism for these unexpected observations is likely shunting of blood away from the placenta to other organs in the face of systemic vasodilation.     

An examination of vascular reactivity during pregnancy in the chronic ewe model

The hind limb vascular responses to angiotensin II and phenylephrine, an alpha-adrenergic agonist, were determined in chronically instrumented pregnant (n = 7) and castrated (n = 6) ewes. On any one day, five doses of one or the other drug were administered directly into the arterial femoral circulation while the perfusion pressure and external iliac blood flow were monitored. The steady-state resistance change (baseline resistance - the resistance calculated during the 3 to 5 minutes of drug infusion) showed a reduction in vascular response to angiotensin II in the pregnant ewes compared to the controls, with no significant differences in response to phenylephrine. When the dynamic (within 40 seconds) rather than the steady-state changes were analyzed, a hyperreactivity to phenylephrine was present in the pregnant animals. These data are an illustration of the complex interactions that are present in the whole-body pressor responses to vasoactive stimuli during pregnancy.     

Coronary and uterine vascular responses to raloxifene in the sheep

OBJECTIVE: We sought to determine whether raloxifene increases coronary and uterine blood flow in ovariectomized ewes. STUDY DESIGN: Twelve ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, coronary blood flow, and uterine blood flow. Sheep received 17beta-estradiol, Estrace, raloxifene, or KY Jelly vehicle on separate days. RESULTS: 17beta-Estradiol increased uterine blood flow from 21 +/- 3 to 254 +/- 36 mL/min and coronary blood flow by 21% +/- 2% within 2 hours. Estrace increased uterine blood flow from 30 +/- 7 to 260 +/- 62 mL/min and coronary blood flow by 8% +/- 4% within 3 hours. Raloxifene increased uterine blood flow from 20 +/- 3 mL/min to 220 +/- 53 mL/min by 6 hours and coronary blood flow by 22% +/- 5% within 24 hours. To determine whether hemodynamic responses were mediated by nitric oxide, L -nitroarginine methyl ester was administered and produced an approximate 50% decrease in uterine blood flow for all 3 compounds. L -Nitroarginine methyl ester attenuated increases in coronary blood flow induced by 17beta-estradiol, Estrace, and raloxifene. CONCLUSION: Raloxifene has significant coronary and uterine vascular effects in the ovariectomized ewe. The coronary and uterine responses are partially mediated by nitric oxide.     

Placental transfer of intravenous nicardipine and disposition into breast milk during the control of hypertension in women with pre-eclampsia

Objective: To assess nicardipine safety for fetuses and neonates. Methods: Nicardipine was measured in maternal plasma (MP), umbilical cord arterial (UaP) and venous (UvP) plasma and breast milk (BrM) of 18 women with severe preeclampsia. Results: Nicardipine was infused for a mean 11.9?±?10.5 days before and 4.6?±?1.6 days after delivery. Nicardipine dose and MP concentration were linearly correlated, as were MP with UaP, UvP, and BrM concentrations. The BrM/MP ratio was 0.06 to 0.30. The mean relative infant dose was 0.082%. Conclusion: Nicardipine is safe for fetuses and neonates due to its low levels of placental transfer and disposition in BrM.     

Maternal ovine placental vascular responses to adenosine

We have examined the effect of adenosine given via retrograde uterine artery catheter at 25 mg/min to nine chronically catheterized near-term sheep pretreated with angiotensin II, 5 micrograms/min, via the jugular vein. Blood flows were measured by the microsphere technique. Flows were measured at rest, after 10 minutes of angiotensin II infusion, and after 1.5 minute of adenosine infusion. Blood pressure increased with angiotensin II infusion from 101 +/- 2.63 to 130 +/- 4.33 mm Hg (p less than 0.05) and then remained unchanged with local adenosine infusion at 129 +/- 4.33 mm Hg (NS). Organ resistances were: Tissue Control Angiotensin II Adenosine Uterine resistance/gm 299 +/- 0.04 767 +/- 83 (p less than 0.05) 355 +/- 37.7 (p less than 0.05) Cotyledonary resistance/gm 37.9 +/- 4.83 48.1 +/- 4.93 (p less than 0.05) 50.10 +/- 5.27 (p less than 0.05) The experimental uterine tissue resistance increased with angiotensin II and showed vasodilation in response to adenosine. The cotyledonary resistance increased with angiotensin II infusion but showed no change in response to adenosine. The maternal-placental response was anomalous. Angiotensin II-induced maternal-placental vasoconstriction cannot be opposed by the exogenous administration of adenosine.     

Placental maturity,hypertensive disorders of pregnancy and birth weight

Objectives: To compare maturity of placentas from women with hypertensive disorders with those from normotensive pregnancies and to determine the relationship between placental maturity (PM) and the diagnosis of small-for-gestational-age (SGA) in the newborns. Materials and methods: We examined placental stained specimens from women with normotensive pregnancies (n?=?100), diagnosis of gestational hypertension (n?=?38), mild (n?=?10), or severe preeclampsia (n?=?34) in an optical microscope. Placental Maturity Index (PMI) was calculated as the number of vasculo-syncytial membranes (VSM) in 1?mm² divided by VSM thickness (µm). Hypermaturity was defined as >90th percentile of the PMI from placentas of normotensive pregnancies. Newborns were classified as SGA, adequate-for-gestational-age (AGA) or large-for-gestational-age (<10th, 10–90th, and >90th percentile from weight for gestational age reference tables, respectively). Results: PMI in preeclamptic women (taking together mild and severe preeclampsia, PMI?=?43.4?±?1.6) was significantly higher than in normotensive women (PMI?=?36?±?2, p?=?0.045). Hypermaturity was more frequent (p?p?=?0.41). The frequency of hypermaturity in placentas from women with gestational hypertension was not statistically different than in normotensive women. Hypermaturity was also more frequent in placentas from SGA (OR?=?2.63, p?Conclusion: The PMI was increased in preeclampsia, but not in gestational hypertension. Placental hypermaturity was also associated with the diagnosis of SGA in newborns. PM might have a role in the relationship between maternal factors and SGA.