Prostacyclin and human foetal circulation

Tissues from human umbilical cord arteries and placental veins generated much greater prostacyclin activity than vessels from normal adults. High prostacyclin generation could contribute to maintaining the low peripheral vascular resistance typical of foetal circulation in which blood pressure is low despite very high cardiac output.     

Prostacyclin and human foetal circulation.

Tissues from human umbilical cord arteries and placental veins generated much greater prostacyclin activity than vessels from normal adults. High prostacyclin generation could contribute to maintaining the low peripheral vascular resistance typical of foetal circulation in which blood pressure is low despite very high cardiac output.     

The distribution and clearances of hormones and metabolites in the circulation of the foetal sheep.

Plasma hormone and metabolite concentrations have been measured in the plasma of blood collected simultaneously from the femoral artery, umbilical vein and carotid artery of the exteriorized foetal sheep. The concentration of vasopressin and catecholamines was consistently lower and of glucose, lactate and corticosteroids consistently higher in the umbilical vein compared with the femoral artery. ACTH concentrations showed no consistent pattern and fluctuated widely at each site, but during synacthen infusion the concentration in the umbilical vein was consistently lower than in the femoral artery. For corticosteroids the concentration in the carotid artery was much lower than that in the umbilical vein; the converse was true for catecholamines. Concentrations in the carotid and femoral artery were similar for all compounds investigated. These results indicate that the placenta is a major site of vasopressin, catecholamine and ACTH clearance and of glucose, lactate and corticosteroid production. The foetal liver is probably a major site of corticosteroid and catecholamine clearance.     

Effects of sedation on the controlled pulmonary circulation

The pulmonary circulatory effects of sedatives and groups of sedatives in dosages commonly employed as pre cardiac catheterization sedatives were evaluated. The sedatives included: meperidine, thiamylal, hydroxyzine, promethazine, meperidine + chlorpromazine + promethazine and meperidine + hydroxyzine. An animal preparation with constant pulmonary blood flow and left atrial pressure was employed. This preparation has the unique advantage of permitting measurement of the active pulmonary vascular resistance change since passive effects are controlled. In order to establish the significance of a given change in active PVR, a dose response relationship for serotonin was established and the effect of the sedatives was calibrated against it. PVR increased following infusion of all sedatives tested except hydroxyzine and chlorpromazine.A technique was detailed to permit subtraction of passive PVR change from total PVR change in intact, unsedated animals. Results of active change in PVR of previous investigations in intact, unsedated animals were compared to the active change observed in this experiment and were found to be similar in direction and magnitude. This investigation stresses the need to consider possible effects of sedatives on the pulmonary circulation.     

Effects of ethanol infusion on foetal EEG and breathing movements

Ethanol (0.3 g/kg and 0.5 g/kg administered over 2 hours) was infused intravenously into 15 chronically instrumented pregnant ewes between 128 to 135 days of gestation (0.85 to 0.92 gestation time, term 147 days). Brainstem dissection above the pons was made in 7 foetuses. Foetal breathing movements were suppressed for 7 hours following a 30 ml ethanol infusion. Low voltage foetal electrocortical activity was suppressed or replaced by an intermediate voltage electrocortical activity for 5 and 3 hours following the 60 ml and 30 ml ethanol infusions, respectively. In brainstem dissected foetuses the effects of ethanol infusion on the foetal EEG were similar. Foetal blood gases and pH were not altered. These data suggest that ethanol moves across the foetal blood-brain barrier and suppresses foetal breathing movements by a direct central mechanism.     

Effects of misoprostol on human circulation

Prostaglandins (PGs) of the E-type are potent vasodilators in most species and in most vascular beds. However, vasoconstrictor effects of PGEs have also been noted at selected sites. This study examined the effects of misoprostol, a PGE₁ analog with antiulcer activity, on the human cardiovascular system. Twenty healthy subjetcs participated in this double-blind, placebo-controlled, parallel group study. Following a 12 hour fast, heart rate, arterial blood pressure, light reflex plethysmography of the finger, resting blood flow volume in the lower arm and leg and peripheral vascular resistance were measured at 10 min. intervals for 1 hour prior to drug administration, to permit calculating baseline values. Misoprostol (400 mcg) or its matching placebo were administered orally, and the measurements were repeated at 10 min. intervals over the next 2 hours. A decrease in leg blood flow volume and a corresponding increase in leg peripheral vascular resistance were noted in the misoprostol group. A statistically significant decrease in heart rate between the two treatment groups was also noted. These small changes were not considered to be of clinical importance. No adverse experiences were reported. In conclusion, a single dose of misoprostol (400 mcg) has no clinically significant vasoconstrictive or vasodilative properties in man.     

Adenine nucleotide compartmentation in foetal rat hepatocytes. Effects of atractyloside, oligomycin, calcium ionophore and adrenergic agonists

In the presence of lactate plus pyruvate, or glucose or alanine as substrates, ATP/ADP ratios in the cytosol were higher than in mitochondria in isolated rat foetal hepatocytes. The cytosolic ATP/ADP ratios were dependent on substrate (lactate + pyruvate greater than glucose greater than alanine). Oleate increased the cytosolic ATP/ADP ratios in the presence of the other substrates studied. Atractyloside decreased the cytosolic ATP/ADP ratios, oligomycin decreasing these values in both compartments. Isoproterenol, phenylephrine and Ca2+ ionophore decreased the cytosolic ATP/ADP ratio, without altering this value in mitochondria.     

Effects of endogenous angiotensin II on the fetal circulation

The role of endogenous angiotensin II in the regulation of the circulation was investigated by infusion of [sar1],[ala8]-angiotensin II, a competitive antagonist of angiotensin II, into fetal sheep with chronically-maintained intravascular catheters. The thesis considered was that angiotensin II may have a greater role in the fetus than in the adult since the autonomic nervous system does not develop fully until late in gestation. Fetal cardiac output and its distribution to various organs and actual blood flows to fetal tissues were determined by the radionuclide-labelled microsphere technique. Intravenous infusion of [sar1], [ala8]-angiotensin II at a rate of 13.95-42.15 microgram/min per kg fetal body weight increased plasma renin activity from a control value of 8.9 +/- 1.6 to 18.9 +/- 3.9 ng/ml per h (SEM). Mean arterial blood pressure fell significantly from a control level of 47 +/- 1.6 to 41 +/- 1.1 mmHg. Blood flow to the unbilical-placental circulation decreased from 239 +/- 27.0 to 198 +/- 20.2 ml/min per kg, but the calculated vascular resistance in the umbilical-placental circulation did not change. Although cardiac output did not change, blood flow to the peripheral circulation, which includes the fetal skin, muscle and and bone and constitutes 75 +/- 0.9% of the total fetal body weight, increased as did flow to the thyroid and adrenal circulations. Endogenous angiotensin II appears to be important in maintaining blood flow to the umbilical-placental circulation by maintaining fetal arterial blood pressure. Angiotensin II exerts this effect by mediating a tonic vasoconstriction primarily in the peripheral circulation.     

Effects of prostaglandins on the cerebral circulation in the coat

The role of prostaglandins in producing cerebrovasodilation during hypercapnia was tested in goats. Cerebral blood flow (CBF) changes with increasing arterial PCO2 were measured before and after prostaglandin synthesis inhibition with indomethacin or ibuprofen. Both drugs produced significant decreases in CBF under control anesthetized conditions but had no significant effect on the cerebrovascular response to increased arterial PCO2. The effects of direct intracerebrovascular infusion of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha) and prostacyclin were also measured. In the dose range tested (0.1-1) microgram/min) PGF2 alpha had no significantly greater than that produced by PGE2. The effectiveness of each compound in producing cerebrovascular changes is consistent with the endogenous distribution of prostaglandins within the brain. These results suggest that prostaglandins, particularly PGI2, may be important in modulating cerebrovascular tone but have no role in increasing CBF during hypercapnia.     

Effects of prostaglandins on the cerebral circulation in the goat

The role of prostaglandins in producing cerebrovasodilation during hypercapnia was tested in goats. Cerebral blood flow (CBF) changes with increasing arterial PCO2 were measured before and after prostaglandin synthesis inhibition with indomethacin or ibuprofen. Both drugs produced significant decreases in CBF under control anesthetized conditions but had no significant effect on the cerebrovascular response to increased arterial PCO2. The effects of direct intracerebrovascular infusion of prostaglandin E₂ (PGE2), prostaglandin F2α (PGF2α) and prostacyclin were also measured. In the dose range tested (0.1–1 ug/min) PGF2α had no significant effect on cerebral blood flow (CBF). Both PGE2 and PGI2 produced an increase in CBF and the increase produced by PGI2 was significantly greater than that produced by PGE2. The effectiveness of each compound in producing cerebrovascular changes is consistent with the endogenous distribution of prostaglandins within the brain. These results suggest that prostaglandins, particularly PGI1, may be important in modulating cerebrovascular tone but have no role in increasing CBF during hypercapnia.     

Effects of octopamine on pulmonary circulation of the pig]

The perfusion of octopamine in pig produces an increase of cardiac output with decrease of pulmonary vascular resistances. The changes in lung circulation depend by a direct action of this drug on nervous control of vascular walls because when the pulmonary shunt increase the effect is not correlated to changes a pattern of breathing.     

Novel approaches to manipulating foetal cells in the maternal circulation for non-invasive prenatal diagnosis of the unborn child

Due to the risks to the foetus with invasive prenatal diagnosis, non-invasive prenatal diagnosis (NIPD) is gaining tremendous interest but no reliable method that can be widely used has been developed to date. Manipulation of foetal cells and foetal cell-free genetic material in the maternal blood are two promising approaches being researched. The manipulation of foetal cells in the maternal circulation is more popular as it can provide complete genetic information of the foetus particularly the diagnosis of aneuploidies. However, the foetal cell numbers in the maternal circulation are small and their enrichment and ex vivo culture remain two major challenges for NIPD. Primitive foetal erythroblasts (pFEs) have been considered as a good potential candidate for early first trimester NIPD but their nature, properties and manipulation to provide adequate cell numbers remain a challenging task and several approaches need to be meticulously evaluated. In this review we describe the current status of NIPD and suggest some novel approaches in manipulating pFEs for future clinical application of NIPD. These novel approaches include (1) understanding the pFE enucleation process, (2) enriching pFE numbers by individual pick-up of pFEs from maternal blood using micromanipulation and microdroplet culture, (3) expansion of pFEs using mitogens and (4) decondensation of the pFE nucleus with histone deacetylase (HDAC) inhibitors followed by reprogramming using gene delivery protocols with/without small reprogramming molecules to improve reprogrammed pFE proliferation rates for successful NIPD.