Beta-adrenoceptive responses in the unanaesthetized ovine foetus.

1. Isoprenaline injection into either the unanaesthetized ovine foetus or the pregnant ewe produced a transient tachycardia and hypotension in either the ewe or the foetus. No evidence was obtained for placental transfer, in either direction, of pharmacologically active isoprenaline.2. Propranolol, when given to the ewe intravenously, produced bradycardia and increased pulse pressure and inhibited the response of both the ewe and her foetus to isoprenaline. Propranolol, when given to the foetus intravenously, produced bradycardia and increased pulse pressure in both the foetus and the ewe, but only the foetal response to isoprenaline was inhibited. These data demonstrated that propranolol crossed the ovine placenta in both directions in a pharmacologically active form.3. Dose-heart rate curves of the foetus and pregnant ewe to isoprenaline and the shift to the right of the isoprenaline dose-response curves by propranolol were similar in both the ewe and the foetus.4. Notwithstanding the similarities between the ewe and foetus in their responses to isoprenaline or propranolol and in the antagonism of isoprenaline by propranolol, the duration of blockade following propranolol administration to the ewe was 2 to 3 times longer in the foetus compared with the ewe.5. Measurement of blood levels of propranolol showed that the maximum concentration of propranolol in foetal plasma was only 5% of that in the pregnant ewe when propranolol was infused into the ewe; the rate of clearance of propranolol was similar from the foetal and maternal plasma.6. From these data the long duration of beta-adrenoceptor blockade in the ovine foetus by propranolol cannot be fully explained. However, these data serve as examples of the dangers involved when extrapolating pharmacological actions of drugs on the foetus purely from data on foetal plasma levels of the drug.7. The data suggest that multiple doses of propranolol, given to maintain a beta-adrenoceptor blockade in the mother, could result in serious cumulative effects in the foetus.

Action of several -adrenoceptor blocking drugs in the pregnant sheep and foetus.

1. The effect of several beta-adrenoceptor blocking drugs on the pregnant ewe and foetus were studied. Bunolol, butidrine, oxprenolol, propranolol and USVP65-24 all crossed the ovine placenta and produced a beta-adrenoceptor blockade in the ovine foetus. AH3474, AY21011 and sotalol did not cross the ovine placenta as assessed by the absence of a beta-blockade in the foetus when these compounds were administered to the pregnant ewe.2. Of the beta-blocking compounds tested, only propranolol and oxprenolol produced a prolonged blockade in the foetus. The beta-blockade with propranolol was of 3 h duration in the ewe and 10 h duration in the foetus. Oxprenolol produced a beta-blockade of 3 h duration in the ewe and 8 h in the foetus.3. The beta-blocking drugs which did cross the ovine placenta were more soluble in organic solvents (ether, chloroform, corn oil and olive oil) than those which did not cross the ovine placenta.

Ethanol kinetics during pregnancy. Study in ewes and their fetuses.

1. Kinetics of placental transfer and elimination of ethanol in maternal and fetal blood and amniotic fluid were studied after iv infusion of ethanol in 3 ewes in the third trimester of pregnancy. 2. Ethanol was transferred rapidly from the maternal to the fetal compartment, and more slowly from these to the amniotic fluid. 3. The kinetics of ethanol elimination from the maternal and fetal circulations were similar, indicating rapid bidirectional transfer between them and elimination from the former only. 4. There was significantly slower elimination of ethanol from the amniotic fluid, with increasing concentrations long after these had started to decline in the maternal and fetal blood. This suggests that the amniotic fluid can act as a reservoir for ethanol storage.

The effects of prolactin on pulmonary maturation in the fetal rabbit.

The effect of ovine prolactin administration on the fetal rabbit pulmonary pressure volume relationship was determined. Using pentobarbital anesthesia, on Day 24 of gestation, a midline incision on the maternal abdomen was made to expose the bicornuate uterus. Fetal rabbits in one horn of the uterus were injected intramuscularly with a dose of 1.0 mg (0.05 ml) of prolactin solution. Similarly, fetuses in the opposite horn were administered an equivalent volume of control vehicle. On Day 26 of gestation, no significant enhancement of lung maturation, as judged from the pressure volume relationship, was found to result from prolactin administration. These results suggest that prolactin does not initiate the secretion of surface active material into the alveolar lumen of the fetal lung in sufficient amounts to induce physiologic maturation of the rabbit fetal lung.

Noradrenergic control of blood vessels in the premature lamb fetus.

Experiments were conducted with fetal lambs of 113-120 days gestation (0.8 term) to assess the integrity of adrenergic neurotransmission at the level of the blood vessels. Regional blood flow and the distribution of blood from the inferior vena cava were compared when the arterial pressure was increased either by an infusion of exogenous noradrenaline or when tyramine was used to evoke a local release of the neurotransmitter. Most vascular beds perfused via the descending aorta were constricted to a similar extent by both drugs although the renal circulation did not respond to tyramine. Noradrenaline increased the distribution of blood from the inferior vena cava to the fetal lungs and both drugs increased placental blood flow. These data indicate that mechanisms for effective adrenergic control of vascular are developed in many organs of the premature lamb fetus by 0.8 of term.

Time course of closure of the ductus venosus in the newborn lamb.

The present study was designed to obtain quantitative data on the extent of portocaval shunting and the time course of closure of the ductus venosus in newborn lambs. Experiments were conducted on eight newborn lambs prepared with chronic portal catheters. The time course of the postnatal closure of the ductus venosus was determined by following the distribution of radiolabelled microspheres injected into the lamb's portal vein 24, 48, 96, and 168 hr after birth. The fraction of the portal blood flow which bypassed the liver was highly variable. In some animals, the ductus venosus was almost completely closed when the first microspheres were injected 24 hr after birth. In others, almost 40% of the portal blood flow bypassed the hepatic circulation at this time. On average, only 77% of the portal blood flow was directed to the liver in the 1-day lambs. In most cases, closure had occurred by 48 hr after birth, but some animals continued to divert a significant fraction of the portal flow away from the hepatic circulation.

The effect of norepinephrine on blood flow through the fetal liver and ductus venosus.

Experiments were conducted with 11 chronically catheterized fetal sheep to determine the effects of norepinephrine on the distribution of umbilical venous blood through the ductus venosus, and within the fetal liver. An intraumbilical infusion of 1.1 microgram/kg/min of norepinephrine increased placental blood flow but did not alter the proportion of this flow that was diverted through the ductus venosus. Under control conditions the umbilical flow to the fetal liver was preferentially distributed to the left side and accounted for 80% of the total hepatic blood flow. Flow through the hepatic artery was negligible. Norepinephrine reduced portal flow but also reduced the asymmetric distribution of hepatic umbilical blood flow by greatly increasing the perfusion of the right side of the fetal liver.

The effects of dopamine of blood pressure and heart rate of the unanesthetized fetal lamb.

The effects of dopamine on blood pressure and heart rate have been studied in continuously cannulated fetal lambs and adult sheep. Drugs were administered by direct intravenous injection into either the fetus or the adult sheep, and blood pressure was measured from an arterial cannula and heart rate was computed from the electrocardiogram (ECG). The magnitude of the fetal pressor response to dopamine increased slightly as the dose of dopamine (1, 10, 50, 100, and 200 mcg. per kilogram was increased, but the magnitude of the response did not increase with advancing gestation (112 to 145 days). However, in the adult sheep, the dose-response relationship was much steeper. In both cases the pressor response was accompanied by a reflex bradycardia that was blocked by atropine (1 mg. per kilogram). In the atropinized fetus, doses of 50 to 200 mcg. per kilogram of dopamine produced tachycardia (30 to 120 b.p.m) and a greater pressor response than that in the unatropinized fetus. Thus, the fetal cardiovascular system is capable of responding to relatively large amounts of dopamine injected as a bolus, suggesting that relatively large amounts of endogenous dopamine would have to be secreted by the mast cells to significantly alter fetal cardiovascular function.

Placental transfer of indomethacin in the rabbit and sheep.

The placental transfer of indomethacin was studied in the rabbit at 30 days of gestation and in the sheep between 120 and 135 days of gestation. Plasma concentrations of indomethacin reached a maximum of 13.7 +/- 1.6 and 10.9 +/- 1.5 microgram/mL in the doe and fetuses, respectively, at 1 h following a maternal subcutaneous injection of 10.0 mg/kg. The maternal plasma concentration of drug decreased rapidly but the fetal plasma concentration of drug remained elevated and exceeded that of the doe before decreasing. Indomethacin became detectable in the amniotic fluid after 2 h, reached a maximum of 3.2 +/- 0.8 microgram/mL at 4 h, and the gradually decreased. The intravenous infusion of 10.0 mg of indomethacin per kilogram over 30 min into a pregnant ewe resulted in a maximal plasma concentration of 13.5 +/- 0.7 microgram/mL in the ewe and 0.6 +/- 0.1 microgram/mL in the fetus at the termination of the infusion. The concentration of indomethacin in the amniotic fluid increased to a maximum of 3.5 +/- 0.5 microgram/mL 150 min after the infusion stopped. There was an increase in the percentage of drug bound by the fetal plasma proteins as gestation advanced. Thus, there exists the possibility that the fetus would be exposed to increasing amounts of indomethacin as term approached.

Effects of tricyclic antidepressants on cardiovascular responses to norepinephrine and phenylephrine during pregnancy.

The effects of imipramine and amitriptyline on the responses of the uteroplacental vasculature to norepinephrine and phenylephrine were investigated in the pregnant ewe. Experiments were performed on conscious animals in which electromagnetic flow transducers were chronically implanted on the uterine arteries. Administered alone, the tricyclic antidepressants had no effect on mean arterial pressure (MAP) or estimated uteroplacental vascular conductance (UPVCe). Following intravenous infusion of either imipramine (1 mg. per kilogram) or amitriptyline (2.5 mg. per kilogram), the pressor response to norepinephrine (1 microgram per kilogram) and the duration of that response were significantly increased (p less than 0.05). In addition, both the duration of the norepinephrine-produced decrease in uteroplacental blood flow (UPBF) and the amplitude of the decrease in UPVCe were enhanced. In contrast, responses to phenylephrine (2.5 microgram per kilogram) were unaffected by prior administration of either imipramine or amitriptyline. Of additional interest were findings suggesting differential sensitivities to alpha-agonists of the uteroplacental compared with other vascular beds. These observations bring attention to the possibility of interactions between endogenous or exogenous norepinephrine and the tricyclic antidepressants and suggest that the possibly unique sensitivities of the uteroplacental bed should be considered when prescribing drugs during pregnancy.

Development of cardiovascular responses to sympathomimetic amines and autonomic blockage in the unanesthetized fetus.

The cardiovascular effects of phenylephrine or ephedrine alone and after autonomic blockade was studied in the chronically cannulated fetal lamb (100-145 days), the newborn lamb, and adult sheep. As gestation advanced, phenylephrine and ephedrine produced an increasing pressor response before and after pretreatment with atropine (1 mg/kg). Compared with the fetus, the magnitudes of the pressor responses were somewhat greater in the newborn and much larger in the adult. Both drugs produced a reflex bradycardia in the unatropinized fetus which in the case of ephedrine was followed by a tachycardia. Pretreatment with atropine resulted in an immediate tachycardia after ephedrine but not after phenylephrine administration. Pretreatment with phentolamine (0.15 mg/kg) produced about a 55% inhibition of the phenylephrine pressor response in both the fetus and adult, suggesting a linear relationship between body weight and number of alpha-adrenergic receptors. Pretreatment with metoprolol blocked the tachycardia associated with ephedrine administration to unatropinized fetuses. In summary, the increase in the magnitude of the pressor response to phenylephrine suggested development of the receptor-effector system. The greater development of the response to ephedrine suggested that there was an increasing amount of noradrenaline being released with advancing gestation.

Responses to electrical stimulation, noradrenaline, serotonin, and vasopressin in the isolated ear artery of the developing lamb and ewe.

Responses of isolated helical strips of ovine ear artery to electrical stimulation of postganglionic adrenergic neurons and exogenous agonists were studied at various stages of development from 110 days of gestation through to adulthood. Only rudimentary responses were observed at 110-115 days of gestation. A parallel development of responses to noradrenaline (NA), serotonin, and lysine vasopressin began sometime after 110-115 days of gestation and continued until 133-137 days of gestation but there was little development of the latter responses until more than 3-5 days post partum. Development of responses to exogenous agonists was incomplete 2-3 weeks post partum. The development of postganglionic adrenergic responses lagged behind those to exogenous NA. Two to three weeks post partum the NA maximal response was one-third that of adult tissue whereas the response to 16 Hz (highest frequency used) was one-sixth that of adult tissue. The NA threshold concentration was lower in arterial strips of adult animals than it was in those of younger animals. The data suggest that development of functional post-ganglionic adrenergic innervation of vascular smooth muscle begins late in gestation and continues well after birth; this development is preceded by development of vascular mechanisms involved in the response to several agonists.

The effects of NA872 on pulmonary maturation in the fetal lamb and rabbit.

The effect of fetal administration of NA872, metabolite VIII of Bisolvon, on the lecithin/sphingomyelin (L/S) ratio of ovine tracheal fluid and of its administration to the pregnant doe on the fetal rabbit pulmonary pressure-volume relationship was determined. Intravenous administration of NA872 in the long-term cannulated lamb fetus in a dose of 4 mg. per day from either 120 to 125 or 125 to 130 days of gestation produced a significant increase in the L/S ratio. Administration of 4 mg. per kilogram per day to the pregnant doe on days 21 to 24 of gestation resulted in significant enhancement of lung maturation in the 25 day fetal rabbit lung as judged from the pressure-volume relationship; a smaller dose, or the same total dose given over shorter time periods, had no significant effect in the 25 day rabbit fetus. Similarly, 8 mg. per kilogram given to the doe on days 26 and 27 produced no over-all significant effect on the 28 day rabbit fetus, although a seasonal effect was found at this age.

Depression of uterine blood flow in response to cord compression in sheep.

Seven conscious chronically cannulated ewes and their fetuses were studied in the third trimester of pregnancy. Compression of the umbilical cord for 4 min, to a degree simulating the occurrence in clinical obstetrics, not only produced the expected fetal hypoxia, acidemia, and cardiovascular effects but also significantly reduced uterine blood flow. In a ewe with twin fetuses, compression of the cord to only one fetus decreased the flow to that horn and had no effect on flow to the other horn. It is postulated that the reduction in uteroplacental flow was due to stimulation of alpha-adrenoceptors in the maternal placental vasculature by catecholamines of fetal organ, or the effects of increased tissue-fluid pressure in the fetal placenta, or a combination of these mechanisms.

Effects of phenylephrine and sodium salicylate on maternal and fetal cardiovascular indices and blood oxygenation in sheep.

Phenylephrine and sodium salicylate, separately and in combination, in doses equivalent to the phenylephrine in one "cold" tablet and the sodium salicylate in three aspirins, were infused into conscious, chronically cannulated ewes in the third trimester of pregnancy. Maternal and fetal indices were recorded before (control), during, and after infusion. Phenylephrine depressed uterine blood flow and maternal heart rate (both, 40% below control) and increased maternal mean arterial blood pressure 50%; in the fetus, it depressed arterial blood Po2 (30%) and blood pH, but increased Paco2 and had little effect on mean arterial blood pressure and heart rate. Salicylate alone had no significant effect on maternal and fetal indices, and sodium salicylate plus phenylephrine produced changes similar to those with phenylephrine alone. We conclude that phenylephrine in the maternal circulation could have detrimental effects on the fetus, particularly when fetal Pao2 is depressed as by cord compression during delivery.

Maternal and fetal cardiovascular indices during fetal hypoxia due to cord compression in chronically cannulated sheep. I. Responses to timolol.

Timolol, one of the newer beta-adrenergic antagonists, has less depressive effects on the heart than propranolol, so that it has the potential for use by pregnant women. In chronically cannulated ewes, timolol at 0.01 and 0.1 mg/kg of body weight induced maternal and fetal bradycardia; the higher dose also depressed uterine blood flow and fetal PaO2. When this higher dose preceded brief compression of the umbilical cord, uterine flow was further depressed and the usual posthypoxia rebound tachycardia did not develop. Both the blocking of fetal responses to hypoxia (precluding detection of fetal distress) and the reduction in uterine flow led us to conclude that timolol taken by a mother could pose particular hazards for her fetus in hypoxic conditions, such as during cord compression at parturition.

Maternal and fetal cardiovascular indices during fetal hypoxia due to cord compression in chronically cannulated sheep. II. Responses to promazine.

Promazine (Sparine) administered to chronically cannulated pregnant ewes caused significant maternal and fetal tachycardia and hypotension, depressed uterine blood flow and fetal Pao2, and increased fetal Paco2. When the drug was given before brief compression of the umbilical cord, uterine flow was more depressed than by compression alone, the fetal pressor response was attenuated, and fetal posthypoxia tachycardia was augmented. We conclude that promazine taken by a mother could have especially deleterious effects on her fetus when the latter's oxygenation is already depressed (e.g., by cord compression), and suggest that the use of promazine during labor be reevaluated.