- Email: [email protected]
The influence of β-adrenergic activity on fetal heart rate and the umbilical circulation during hypoxia in fetal sheep
592
Shoupe,
Kumar,
and Lobo
November Am. J. Obstet.
14. Costin, G.. Goebelsmann, U., and Kogut, M.: Sexual precosity due to a testosterone-producing adrenal tumor, J. Clin. Endocrinol. Metab. 45:912, 1977. 15. Lobo, E. A., Kletzky, 0. A., Kaptein, E. M., and Goebelsmann, U.: Prolactin modulation of dehydroepiandrosterone sulfate secretion. AM. J. OBSTET. GYNECOL. 138: 632, 1980. 16. Thorneycroft, I. H., Ribeiro, W. 0.. Stone, S., and Mishell, D. R., Jr.: A radioimmunoassay of androstenedione. Steroids 21:111, 1973. 17. Goebelsmann, U., Arce, J. J., Thorneycroft, I. H., and Mishell, D. R., Jr.: Serum testosterone concentrations in women throughout the menstrual cycle and following HCG administration. AM. J. OBSTET. GYNECOL. 119:445. 1974. 18. Stumpf, P., Nakamura, R. M., Mishell, D. R., Jr.: Changes in physiologically free circulating estradiol and testosterone during exposure to levonorgestrel, J. Clin. Endocrinol. Metab. 52:138, 1981. D. R., Jr., Nakamura, R. M., Crosignani, P. G., 19. Mishell, Stone, S. G., Kharma, K., Nagata, Y., Thorneycroft, I. H.: Serum gonadotropin and steroid patterns during the normal menstrual cycle, AM. J. OBSTET. GYNECOL. 111: 60, 1971. 20. Abraham, G. E., Buster, J. E., Kyle, F. W., Corrales, P. C., and Teller, R. C.: Radioimmunoassay of plasma pregnenolone. 17-hydroxypregnenolone and dehydroepiandrosterone under various physiological conditions, J. Clin. Endocrinol. Metab. 37:140, 1973. 21. Anderson, D. C., Hopper, B. R., Lasley, B. L., and Yen, S. C. C.: A simple method for the assay of eight steroids in small volumes of plasma, Steroids 28:179, 1976. 22. Van Damme, M. P., Robertson, D. M., and Diczfalusy, E.: An improved in vitro bioassay method for measuring luteinizing hormone (LH) activity using mouse leydig cell preparations, Acta Endocrinol. 77:655, 1974.
23.
24.
25.
26.
27.
28.
29.
30.
1, 1983 Gynecol.
Gambhir, K., Archer, J. A., and Carter, L.: Insulin radioreceptor assay for human erythrocytes, Clin. Chem. 23:1590, 1977. VanHouten, M., Posner, 8. I., Kopriwa, B. M., and Brawer, J. R.: Insulin binding sites localized to nerve terminals in rat median eminence and arcuate nucleaus. Science 207:1081, 1980. Nakai, Y., Plant, T. M., Hess, D. L., Keogh, E. J., and Knobil, E.: On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey, Endocrinology 102:1008, 1978. Norman, R. L., and Spies, H. G.: Brain lesions in infant female rhesus monkeys: Effects on menarche and first ovulation and on diurnal rhythms of prolactin and cortisol, Endocrinology LOS:1 723, 1981. Krey, L. C., Hess, D. L., and Butler, W. R., EspinosaCampos, J., Lu, K. H., Piva, F., Plant, T. M., Knobil, E.: Medial basal hypothalamic disconnection and the onset of puberty in the female rhesus monkey, Endocrinology 108:1944, 1981. Wildt, L., Marshall, G., and Knobil, E.: Experimental induction of puberty in the infantile female rhesus monkey, Science 207:1373, 1980. Adashi, E. Y., Hsueh, A. J. W., and Yen, S. S. C.: Insulin enhancement of luteinizing hormone and folliclestimulating hormone release by cultured pituitary cells, Endocrinology 108:1441, 1981. Steiner, R. A., Cameron, J. L., McNeill, T. H., Clifton, D. K., and Bremner, W. J.: Metabolic signals for the onset of puberty, in Norman, R. L., editor: Neuroendocrine Aspects of Reproduction, New York, 1983, Academic Press, Inc.
The influence of p-adrenergic activity on fetal heart rate and the umbilical circulation during hypoxia in fetal sheep J. T. Parer, San Fronci,w,
M.D.,
Ph.D.
California
To determine the importance of p-adrenergic activity during hypoxia in the fetus, 13 studies were carried out on seven chronically instrumented sheep at nine tenths of gestation. Hypoxia was induced by having the mother breathe gas mixtures that resulted in a reduction of maternal arterial oxygen tension to 32 mm Hg. Hypoxia resulted in a decrease in fetal heart rate (165 ? 17 to 140 2 26 bpm) and fetal oxygen consumption (5.9 2 1.3 to 3.0 2 1.5 ml/min/kg) and increases in fetal arterial and umbilical venous pressures. There was no change in umbilical blood flow (209 ? 56 ml/min/kg). Propranolol, 1.1 ml/kg, was rapidly infused into a fetal vein to achieve complete P-adrenergic blockade. Umbilical vascular resistance increased significantly, fetal heart rate decreased to 112 ? 22 bpm, and umbilical blood flow decreased to 165 -c 73 mliminlkg. There was no further decrease in fetal oxygen consumption. These decreases are approximately twice those seen after propranolol without hypoxia. These findings suggest that during hypoxia there is an increase in p-adrenergic activity, which tends to maintain fetal heart rate and umbilical blood flow. This activity counteracts (AM. J. OBSTET. GYNECOL. 147592,
the increase 1963.)
in vagal
activity
From the Department of Obstetrics, Gynecology and Reproductive Sciences and the Cardiovascular Research Institute, University ?f Calafornia San Francisco. Supported by National Institutes of Health Grants HD 09980 and HD 13764.
592
with hypoxia,
which
decreases
heart
rate.
Sponsored by the Society for Gynecologic Investigation. Reprint requests: J. T. Parer, M.D., Department of Obstetrics and Gynecology, Room M-1480, University of Cal$ornia San Francisco, San Francisco, CalifMnia 94143.
Volume Number
147 5
The autonomic nervous system mediates a number of the hemodynamic changes seen with fetal hypoxia. The striking bradycardia seen during acute hypoxia in the previously normoxic fetus is due to an approximately fivefold increase in vagal chronotropic activity during hypoxia.’ a-Adrenergic activity also increases during hypoxia, and this is at least partly responsible for the redistribution of blood flow to fetal organs during hypoxia.* In the present study we have used the P-receptor-blocking agent propranolol to examine the influence of fi-adrenergic activity during hypoxia on fetal heart rate, fetal blood pressure, umbilical circulation, and fetal oxygen consumption. Material and methods Seven cross-bred Western ewes of 122 to 134 days’ gestational age (mean, 127 ? 3 SD) at the time of study were used. They were fasted for 24 to 48 hours before operation. The surgical procedures were carried out under aseptic conditions, and a spinal anesthetic with supplemental thiopental was used. Catheters were placed in the maternal hind limb artery, amniotic cavity, fetal distal aorta (representative of umbilical arterial blood), and common umbilical vein.3 An electromagnetic flow transducer was placed on the common portion of the umbilical artery.’ Blood flow was measured by a Statham SP2202 blood flowmeter, and blood pressures were determined with Statham P23Db pressure transducers. The zero position of all strain gauges, including that of the amniotic cavity, was at a marked point in the angle between the rear leg and abdomen of the sheep. All of the factors were recorded on a Beckman R411 Dynograph. Umbilical vascular resistance was calculated as the difference between umbilical arterial and venous pressures divided by umbilical blood flow. Blood gases and pH were measured at 39” C with Radiometer electrodes. Hemoglobin was measured spectrophotometrically as cyanmethemoglobin and hematocrit was determined by a microcentrifuge. The oxygen content was measured by a technique which requires the measurement of oxygen tension after release of the oxygen attached to hemoglobin with a deoxygenated solution containing carbon monoxide.5 The blood sample required for this is approximately 25 ~1. The accuracy of this technique was attested to by an almost exact correlation of values obtained on the same blood with the Van Slyke manometric apparatus. The correlation coefficient was 0.999, and all values agreed within 0.2 ml/l00 ml (n = 24). Saturation of hemoglobin with oxygen was calculated by dividing the oxygen content by the product of hemoglobin concentration and 1.34. Oxygen consumption was calculated as the product of umbilical blood flow and the umbilical venous minus the distal aortic blood oxygen content difference.
p-Adrenergic
activity
during
hypoxia
593
Antibiotics (400,000 U of penicillin and 500 mg of dihydrostreptomycin) were administered intramuscularly to the mother on the day of operation and for the first 5 days postoperatively. For the first week postoperatively penicillin (1 million units) and kanamycin (250 mg) were infused into the amniotic cavity. The seven animals were used in 13 individual studies, a mean of 6.2 days after operation (range, 2 to 13 days). There were one to four studies on any one sheep, and there was at least a P-day interval between studies on the same sheep. Before the study began the sheep was placed in the holding pen for several hours, and the laboratory was kept quiet. Catheters and electrodes were attached to the recorder. A plastic bag with a high flow of room air (greater than 22 L/min) passing through it was placed over the head of the sheep. In a preliminary study, 10 sets of determinations of cardiorespiratory measurements were made before the plastic bag was placed over the head of the sheep and it was shown that these values did not differ significantly. Hence, the control measurements were those with the plastic bag already in place. After the control sampling and measurements, a hypoxic gas mixture was substituted for room air without manipulation of the sheep. The hypoxic gas mixtures were made by channeling nitrogen and room air plus 5% carbon dioxide through a Y tube at flow rates above 22 L/min. The degree of hypoxia was adjusted to achieve a mean maternal arterial blood oxygen tension of 30 to 35 mm Hg. Samples were drawn at an average of 37 ? 9 (SD) min after the hypoxia was begun (range, 22 to 53 minutes), as this time range had been shown previously as giving values representative of stable conditions.6 Seven minutes after this sampling, propranolol (1 mg/kg of estimated fetal weight) was injected as a bolus into the umbilical vein or fetal inferior vena cava. After final estimation or measurement of fetal weight, it was found that the actual dosage was 1.14 mg/kg of fetal weight. Total /3-adrenergic blockade had been demonstrated previously with this dosage,i and we confirmed this total blockade by demonstrating the absence of any response to intravenous isoproterenol (0.1 mgikg of fetal weight) and the absence of any response to further bolus injections of intravenous propranolol up to 10 minutes after the first bolus. Sampling for the “propranolol” period occurred an average of 4.5 + 2 minutes (range, 1 to 7 minutes) after injection of the drug. An average of 9 2 3 minutes after this sampling, atropine, 200 pglkg of estimated fetal weight, was injected intravenously, and sampling was again carried out at 5.0 + 2.5 minutes afterward. This dosage had previously been shown to produce complete parasympathetic blockade. ‘3 7 The ewe was then allowed to breathe room air, and a further set of samples and
594
Parer
Table
November Am. J. Obstet.
I. Maternal
arterial
features
during
hypoxia,
propranolol,
Control
content (ml O,/lOO ml)
Oxygen Oxygen
saturation
6.5 _’ 1.3
L-p 91 2 6
pressure
(mm
98.5
Hg)
dioxide pressure
Base excess (mEq/L) Mean arterial blood pressure (mm Hg) Heart rate (bpm)
-c 6.2
sheep;
Oxygen content (ml O,/lOO Umbilical venous arterial
saturation
(%)
Oxygen pressure (mm Umbilical venous Umbilical
532
11
54 I? 14
2 4.7
31.6
rt 5.2
32.4
2 6.3
_’ 8.8 25.1 p < 0.01 d 7.48 i- 0.05 7.58 -p < 0.001+0.3 + 5.0 + 1.4 85 2 10 81 -p
2 2.9
25.5
k 4.2
24.0
2 4.0
2 0.07
7.56
k 0.06
7.57
?I 0.07
-
2 4.0 k 8
+0.3 + 3.9 81 f 9
-+ 35
126 + 27
-p < O.OlA
-p
0 + 2.9 802 10 115 2 21
< 0.001-
and atropine
on umbilical
venous and distal aortic blood
gases of the
Hypoxia and propranolol
Hypoxia plus propranolol plus atropine
3.5 zk 0.6
3.8 _) 1.0
3.3 2 0.9
1.9 + 0.8
2.1 4 0.7
1.9 + 1.1
28 2 10
31 2 12
27 5 10
15 t 6
17 t
16 -c 9
Hypoxia
ml) 9.4 2 1.2* L-p 6.0 2 1.1 L-p 73 -t 14 L-p 48 t 11 L-p
< 0.001< 0.001< 0.0019
< 0.001-
Fig)
arterial
Carbon dioxide pressure (mm Hg) Umbilical venous Umbilical
1.7
32.4
Control
Oxygen
f
13 studies.
Table II. Effects of propranolol hypoxic fetus
Umbilical
6.7
< 0.001-
-p
6.3 2 1.3
54 2 9
32.2
Hg)
Hypoxia fh.s prvprarwlol ph.5 atropine
< 0.001-
-p
Carbon (mm PH
to the fetus
< 0.001-
-p
Oxygen
administration Hypoxia +.s pmpranolol
Hypoxia
11.1 2 l.fP
(%)
and atropine
1,1983 Gynecol.
arterial
30.3 19.5
42.1 46.4
rt 4.2 -p _’ 1.0
< 0.001-
L-p
< 0.001’
t- 4.1 L-p 2 5.8 -
12.8 t- 2.5 9.2 k 2.4
33.8 < 0.001-
f
40.8
+ 4.4 -
I 7.32
2 L--p 0.08 I 2 0.07
14.1
2 2.4
-
3.8 -
p 4 0.01 -
14.1 ‘- 2.0 p < 0.02
10.2
2 2.3
9.2 2 3.0
31.6
+ 4.0
33.7
2 3.6
4,6
40.8
*
p < 0.02 39.1_ p < 0.02 T
4.1
PH Umbilical
venous
7.40
+I 0.04 p < 0.0,
Umbilical
arterial
7.38
f
0.04
-p Base excess (mEq/L) Umbilical venous
+ 1 i
3.9 -p
Umbilical
arterial
+2.0
sheep;
13 studies.
-p < 0.001t------p -7.8
< 0.001’
_’ 4.5 I--P
Seven **SD.
7.28
< 0.001-
-5.8 < 0.001-
< o.017.281+10.08p< p < 0.001 7.24 2 0.08
k 4.4 L-p t------p 2 5.9 L-p I
- ll.?
L-p < 0.001
0.0017.24
0.08 7.19
< 0.001’
k 3.2
t
0.09
- 12.3
+ 4.3
- 11.8
k 4.9
< 0.001’ < 0.001r - 10.2 k 4.2 < 0.001’ -p p < 0.001
< 0.01’
Volume Number
Table
P-Adrenergic
147 5
III.
Effects of propranolol
and atropine
on the umbilical
circulation
activity during hypoxia
and heart rate of the hypoxic Hypoxiu
Control
Hypoxia
Umbilical blood flow (ml/min/kg) Arterial blood pressure (mm Hg)
209 ‘- 58* 53 2 3 -p
< 0.001-
217 f 90 -p 60 2 6
Umbilical venous blood pressure (mm Hg) Intra-amniotic pressure (mm W Umbilical vascular resistance [mm Hg/(ml/ min/kg)] Fetal heart rate (bpm)
19 ‘- 5 -p 922
< 0.01-
0.17 2 0.05 165 i- 17 -p
prqbranolol
-p 24 f 6 923
9k3
140 lr. 28 -p
< 0.01-
fetus plus
propranolol plus atropine
Plus
173 2 73 -p 59 2 5 -p < 0.02 24 2 6
0.18 2 0.06 -p < 0.001-
Hypoxia
595
199 + 74 < 0.00163 + 6
< 0.01-
, 24 2 6 B-3
0.22 * 0.09
0.20 t 0.07
< 0.01113 f 21 < o.oolp
175 t 17 < 0.001-
Seven sheep; 13 studies. **SD. measurements was taken; these were designated “recovery” values, 60 t 17 minutes after cessation of hypoxia. The total duration of hypoxia was 68 2 11 minutes. Fetal weight was measured at delivery or death, and estimations of in utero weight were made by extrapolation of growth curves.’ Mean fetal weight was 2,627 2 413 gm. Student’s t test, either unpaired or, where appropriate, paired, was used for statistical comparison of treatments. To reduce the type 1 error, due to multiple comparisons with a single control, the level of significance was divided by the number of comparisons. The null hypothesis was rejected when P < 0.02.
Results Maternal
arterial
factors
during
hypoxia
and
fetal
During imposed hypoxia there was a decrease in oxygen tension to a mean of 32.4 mm Hg and appropriate decreases in oxygen content and saturation (Table I). Despite the added carbon dioxide in inspired air, there was a decrease in carbon dioxide tension, probably due to hypoxic hyperventilation. This gave rise to an alkalosis, which was respiratory, and little change in base excess. There was a slight, though significant, decrease in mean arterial blood pressure with hypoxia, and a marked increase in heart rate. During hypoxia and fetal administration of drugs there was relative stability of oxygen, carbon dioxide, and acid base measurements. The mean arterial blood pressure was unchanged, but there was a small decrease in heart rate (Table I). The mean maternal hematocrit in the control period administration
of propranolol
and
atropine.
was 26.9% ? 2.7%, and hemog-lobin 8.2 -+ 0.8 gm/dl. Oxygen, umbilical pranolol
carbon
dioxide,
venous and and atropine
and
concentration acid-base
distal aortic administration
was
values
in
blood during proto the hypoxic
fetus. Oxygen pressure, content, and saturation decreased during maternal hypoxia (Table II). These values were relatively stable after administration of the drugs, although there was a slight and statistically significant increase in oxygen pressure after propranolol. Carbon dioxide tension decreased in both umbilical blood samples with hypoxia, as it had in maternal arterial blood. There was a progressive acidemia noted in both umbilical venous and umbilical arterial blood, which was accompanied by a decrease in base excess. The mean fetal blood hematocrit in the control period was 32.4% 2 6.8%, and hemoglobin concentration was 9.3 + 2.0 gm/dl. Umbilical
circulation
propranolol
and
and atropine
fetal
heart
rate
administration
during to
the
The response to hypoxia-a stable umbilical blood flow, bradycardia, and increases in fetal arterial and umbilical venous pressures (Table III)was similar to observations previously reported from the laboratory.” After propranolol administration to the fetus, there was a decrease in umbilical blood flow and bradycardia, and the calculated vascular resistance increased. There was no change in umbilical vessel blood pressure (Table III). After atropine administration, heart rate returned to the above control values, and there was an increase in arterial blood pressure.
hypoxic
Oxygen atropine
fetus.
consumption administration
following to the
hypoxic
propranolol
and
fetus.
During
596
Tabie
Parer
IV. Effects of propranolol
November Am. J. Obstet.
and atropine
on oxygenation
of the hypoxic
fetus Hypoxia
Umbilical blood flow (ml/min/kg) Umbilical venous-arterial oxygen difference (ml O,/lOO ml) Oxygen consumption (ml/minlkg)
209 ” 5s*
217 * 90 L-p
3.3 2 0.9
5.9 2 1.3 -p
1.5 -c 0.7
Hypoxia plus propranolol ph.5 a&opine
Plm
Hypoxia
Control
1, 1983 Gynecol.
propranolol
173 * 73 <
199 + 74 < 0.001-
o.ol--~~p . +
.
1.4 f
0.7
2.4 f
1.4
p < 0.0013.0 2 1.5
2.6 2 1.3
< 0.01-
Seven sheep; 13 studies. **SD.
hypoxia, fetal oxygen consumption decreased to 51% of the control value, because of a narrowing of the venous-arterial oxygen concentration difference. After propranolol administration, there was no significant change in fetal oxygen consumption, despite a 20% drop in umbilical blood flow. After the addition of atropine, there was an increase in umbilical blood flow toward normal but, again, no significant change in oxygen consumption. Comment In the fetus, the major change in the umbilical blood gases occurred in response to hypoxia with relatively smaller changes thereafter (Tables II and IV). The pH and base excess, however, showed a progressive decline, almost certainly as a result of the metabolic acidosis. which was due to the continued duration of hypoxia, as had been described previously.” The interpretation of drug effects must, therefore, be made with due regard to these progressive changes, and the present results can be compared to previous studies of the same fetal preparation without any drug treatment.” The major maternal changes seen were those directly attributable to hypoxia. The changes in maternal heart rate were progressive and most likely due to the continued duration of hypoxia rather than to the drugs. The most striking effect of propranolol is on fetal heart rate and umbilical blood flow, where there were decreases of 1557, and 2070, respectively. In the normoxie sheep fetus we had demonstrated that proprano101 caused only a 6%) drop in heart rate and a 13%) decrease in umbilical blood flo~.~ This implies that during hypoxia there is an increase in P-adrenergic activity, which results in a tendency to maintain fetal heart rate and umbilical blood flow. The umbilical blood flow could be maintained because of /3-adrenergic vasodilatation of the placental vascular bed or by the inotropic action of sympathetic activity in maintaining cardiac output. In support of this, Cohn and associates” have shown that, under hypoxic conditions more severe than those reported here (judging by distal aortic oxy-
gen tension), p-adrenergic activity assists in maintaining the cardiac output and umbilical blood flow. By comparison with our results’ and those of Oakes and associates,” this activity is greater than that found during normoxia. In the present study, fetal oxygen consumption did not decrease significantly after p-adrenergic blockade. It is not known if this would be so under more severe degrees of hypoxia, such as that reported by Cohn and associates,‘” where umbilical blood flow decreased by approximately 30%. Under such conditions, it is likely that the venous-arterial oxygen concentration difference cannot widen further, so fetal oxygen consumption would decrease.6 By adding parasympathetic blockade to P-adrenergic blockade, we have been able to observe the combined effects of these branches of the autonomic nervous system in maintenance of fetal oxygenation during hypoxia. The parasympathetic contribution to maintenance of oxygenation under these conditions is minimal but its role in decreasing heart rate may be more important. This could conceivably contribute to the fetal adaptation to hypoxia by limiting myocardial work and oxygen consumption,’ thus prolonging the duration of tolerance by the fetus to a given degree of hypoxia. Myocardial blood flow is increased in the absence of vagal activity in the fetus subjected to mild or severe hypoxia,12 so the vagal activity can be considered to be contributing to the minimizing of myocardial work. It is of interest that the net fetal heart rate is slightly elevated above normal in the presence of parasympathetic and P-adrenergic blockade in the normoxic fetus,H and the same is true in the hypoxic fetus (Table III). This suggests that the baseline heart rate consists solely of the net result of these two influences. The clinical use of propranolol for maternal indications has had both support and criticism. In the past it has been difficult to separate out fetal effects due to the antecedent maternal illness requiring drug treatment and the direct effects of the drug itself.13 Most recent authorities agree with its use in moderate doses when
Volume Number
147 5
p-Adrenergic
indicated,i4 demonstrate
and its
mothers.is the doses
that
present
study
possible
producing
is clear tive thus
The
maximum
there have been published efficacy in hypertensive
total
blockade
propranolol
effects of decreasing
is of help
acute
in the
removes
P-adrenergic the degree
effects
trials pregnant
to
in determining of
the
hypoxic
some
of the
drug, fetus.
at It
protec-
activity during asphyxia, of “reserve” of the fetus.
REFERENCES
activity
during
Bound
volumes
available
to subscribers
Bound volumes of the AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY are available to subscribers (only) for the 1983 issues from the Publisher, at a cost of $70.95 ($90.00 international) for Vol. 145 (January-April), Vol. 146 (May-August), and Vol. 147 (September-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the JOURNAL name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mr. Deans Lynch at The C. V. Mosby Company, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA.
Subscriptions must be in force to qualify. a regular JOURNAL subscription.
597
7. Vapaavouri, E. K., Shinebourne, E. A., Williams, R. L., Heymann, M. A., and Rudolph, A. M.: Development of cardiovascular responses to autonomic blockade in intact fetal and neonatal lambs, Biol. Neonate 22: 177, 1973. 8. Winters, L. M., and Feuffel, G.: Studies on the physiology of reproduction in the sheep. IV. Fetal development, University of Minnesota Agriculture Experiment Station Technical Bulletin, Minneapolis, 1936, University of Minnesota, pp. 118. 9. Harris, J. L., Krueger, T. R., and Parer, J. T.: The effect of parasympathetic and /3-adrenergic blockade on the umbilical circulation in the unanesthetized fetal sheep,L Gynecol. Obstet. Invest. lOt306, 1979. 10. Cohn. H. E.. Piasecki. G. I.. and Iackson. B. T.: The effect of /3-adrenergic stimula~o’n on fetal cardiovascular function during hypoxemia, AM. J. OBSTET. GYNECOL. 144~810, 1982. 11. Oakes, G. K., Walker, A. M., Ehrenkranz, R. A., and Chez, R. A.: Effect of propranolol infusion on the umbilical and uterine circulations of pregnant sheep, AM. J. OBSTET. GYNECOL. 126:1038, 1976. 12. Cohn, H. E., Piasecki, G. J., and Jackson, B. T.: The effect of fetal heart rate on cardiovascular function during hypoxemia, AM. J. OBSTET. GYNECOL. 13&l 190, 1980. 13. Datta, S., Kitzmiller, J. L., Ostheimer, G. W., and Schoenbaum, S. C.: Propranolol and parturition, Obstet. Gynecol. 51:577, 1978. 14. Rubin, P. C.: Beta-blockers in pregnancy, N. Engl. J. Med. 305:1323, 1981. 15. Gallery, E. D. M., Saunders, D. M., Hunyor, S. N., and Gyory, A. Z.: Randomized comparison of methyldopa and oxprenolol for treatment of hypertension in pregnancy, Br. Med. J. 1:1591, 1979. .A
1. Parer, J. T.: The effect of atropine on heart rate and oxygen consumption of the hypoxic fetus. Submitted for publication. 2. Reuss, M. L., Parer, J. T., Harris, J. L., and Krueger, T. R.: Hemodynamic effects of alpha-adrenergic blockade during hypoxia in fetal sheep, AM. J. OBSTET. GYNECOL. 142:410, 1982. 3. Young, W. P., Greasy, R. K., and Rudolph, A. M.: Catheterization of the common umbilical vein for chronic fetal lamb studies, J. Appl. Physiol. 37:620, 1974. 4. Berman, W., Goodlin, R. C., Heymann, M. A., and Rudolph, A. M.: Measurement of umbilical blood flow in fetal lambs in utero, J. Appl. Physiol. 39:1056, 1975. 5. Duke, G. S., and Newhouse, Y.: Micromethod for measuring blood oxygen content by determining oxygen tension after saturation with carbon monoxide, Am. Rev. Respir. Dis. 110:814, 1974. 6. Parer, J. T.: The effect of acute maternal hypoxia on fetal oxygenation and the umbilical circulation in the sheep, Eur. J. Obstet. Gynecol. Reprod. Biol. 10:125, 1980.
hypoxia
Bound
volumes
are not available
in place of
Shoupe,
Kumar,
and Lobo
November Am. J. Obstet.
14. Costin, G.. Goebelsmann, U., and Kogut, M.: Sexual precosity due to a testosterone-producing adrenal tumor, J. Clin. Endocrinol. Metab. 45:912, 1977. 15. Lobo, E. A., Kletzky, 0. A., Kaptein, E. M., and Goebelsmann, U.: Prolactin modulation of dehydroepiandrosterone sulfate secretion. AM. J. OBSTET. GYNECOL. 138: 632, 1980. 16. Thorneycroft, I. H., Ribeiro, W. 0.. Stone, S., and Mishell, D. R., Jr.: A radioimmunoassay of androstenedione. Steroids 21:111, 1973. 17. Goebelsmann, U., Arce, J. J., Thorneycroft, I. H., and Mishell, D. R., Jr.: Serum testosterone concentrations in women throughout the menstrual cycle and following HCG administration. AM. J. OBSTET. GYNECOL. 119:445. 1974. 18. Stumpf, P., Nakamura, R. M., Mishell, D. R., Jr.: Changes in physiologically free circulating estradiol and testosterone during exposure to levonorgestrel, J. Clin. Endocrinol. Metab. 52:138, 1981. D. R., Jr., Nakamura, R. M., Crosignani, P. G., 19. Mishell, Stone, S. G., Kharma, K., Nagata, Y., Thorneycroft, I. H.: Serum gonadotropin and steroid patterns during the normal menstrual cycle, AM. J. OBSTET. GYNECOL. 111: 60, 1971. 20. Abraham, G. E., Buster, J. E., Kyle, F. W., Corrales, P. C., and Teller, R. C.: Radioimmunoassay of plasma pregnenolone. 17-hydroxypregnenolone and dehydroepiandrosterone under various physiological conditions, J. Clin. Endocrinol. Metab. 37:140, 1973. 21. Anderson, D. C., Hopper, B. R., Lasley, B. L., and Yen, S. C. C.: A simple method for the assay of eight steroids in small volumes of plasma, Steroids 28:179, 1976. 22. Van Damme, M. P., Robertson, D. M., and Diczfalusy, E.: An improved in vitro bioassay method for measuring luteinizing hormone (LH) activity using mouse leydig cell preparations, Acta Endocrinol. 77:655, 1974.
23.
24.
25.
26.
27.
28.
29.
30.
1, 1983 Gynecol.
Gambhir, K., Archer, J. A., and Carter, L.: Insulin radioreceptor assay for human erythrocytes, Clin. Chem. 23:1590, 1977. VanHouten, M., Posner, 8. I., Kopriwa, B. M., and Brawer, J. R.: Insulin binding sites localized to nerve terminals in rat median eminence and arcuate nucleaus. Science 207:1081, 1980. Nakai, Y., Plant, T. M., Hess, D. L., Keogh, E. J., and Knobil, E.: On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey, Endocrinology 102:1008, 1978. Norman, R. L., and Spies, H. G.: Brain lesions in infant female rhesus monkeys: Effects on menarche and first ovulation and on diurnal rhythms of prolactin and cortisol, Endocrinology LOS:1 723, 1981. Krey, L. C., Hess, D. L., and Butler, W. R., EspinosaCampos, J., Lu, K. H., Piva, F., Plant, T. M., Knobil, E.: Medial basal hypothalamic disconnection and the onset of puberty in the female rhesus monkey, Endocrinology 108:1944, 1981. Wildt, L., Marshall, G., and Knobil, E.: Experimental induction of puberty in the infantile female rhesus monkey, Science 207:1373, 1980. Adashi, E. Y., Hsueh, A. J. W., and Yen, S. S. C.: Insulin enhancement of luteinizing hormone and folliclestimulating hormone release by cultured pituitary cells, Endocrinology 108:1441, 1981. Steiner, R. A., Cameron, J. L., McNeill, T. H., Clifton, D. K., and Bremner, W. J.: Metabolic signals for the onset of puberty, in Norman, R. L., editor: Neuroendocrine Aspects of Reproduction, New York, 1983, Academic Press, Inc.
The influence of p-adrenergic activity on fetal heart rate and the umbilical circulation during hypoxia in fetal sheep J. T. Parer, San Fronci,w,
M.D.,
Ph.D.
California
To determine the importance of p-adrenergic activity during hypoxia in the fetus, 13 studies were carried out on seven chronically instrumented sheep at nine tenths of gestation. Hypoxia was induced by having the mother breathe gas mixtures that resulted in a reduction of maternal arterial oxygen tension to 32 mm Hg. Hypoxia resulted in a decrease in fetal heart rate (165 ? 17 to 140 2 26 bpm) and fetal oxygen consumption (5.9 2 1.3 to 3.0 2 1.5 ml/min/kg) and increases in fetal arterial and umbilical venous pressures. There was no change in umbilical blood flow (209 ? 56 ml/min/kg). Propranolol, 1.1 ml/kg, was rapidly infused into a fetal vein to achieve complete P-adrenergic blockade. Umbilical vascular resistance increased significantly, fetal heart rate decreased to 112 ? 22 bpm, and umbilical blood flow decreased to 165 -c 73 mliminlkg. There was no further decrease in fetal oxygen consumption. These decreases are approximately twice those seen after propranolol without hypoxia. These findings suggest that during hypoxia there is an increase in p-adrenergic activity, which tends to maintain fetal heart rate and umbilical blood flow. This activity counteracts (AM. J. OBSTET. GYNECOL. 147592,
the increase 1963.)
in vagal
activity
From the Department of Obstetrics, Gynecology and Reproductive Sciences and the Cardiovascular Research Institute, University ?f Calafornia San Francisco. Supported by National Institutes of Health Grants HD 09980 and HD 13764.
592
with hypoxia,
which
decreases
heart
rate.
Sponsored by the Society for Gynecologic Investigation. Reprint requests: J. T. Parer, M.D., Department of Obstetrics and Gynecology, Room M-1480, University of Cal$ornia San Francisco, San Francisco, CalifMnia 94143.
Volume Number
147 5
The autonomic nervous system mediates a number of the hemodynamic changes seen with fetal hypoxia. The striking bradycardia seen during acute hypoxia in the previously normoxic fetus is due to an approximately fivefold increase in vagal chronotropic activity during hypoxia.’ a-Adrenergic activity also increases during hypoxia, and this is at least partly responsible for the redistribution of blood flow to fetal organs during hypoxia.* In the present study we have used the P-receptor-blocking agent propranolol to examine the influence of fi-adrenergic activity during hypoxia on fetal heart rate, fetal blood pressure, umbilical circulation, and fetal oxygen consumption. Material and methods Seven cross-bred Western ewes of 122 to 134 days’ gestational age (mean, 127 ? 3 SD) at the time of study were used. They were fasted for 24 to 48 hours before operation. The surgical procedures were carried out under aseptic conditions, and a spinal anesthetic with supplemental thiopental was used. Catheters were placed in the maternal hind limb artery, amniotic cavity, fetal distal aorta (representative of umbilical arterial blood), and common umbilical vein.3 An electromagnetic flow transducer was placed on the common portion of the umbilical artery.’ Blood flow was measured by a Statham SP2202 blood flowmeter, and blood pressures were determined with Statham P23Db pressure transducers. The zero position of all strain gauges, including that of the amniotic cavity, was at a marked point in the angle between the rear leg and abdomen of the sheep. All of the factors were recorded on a Beckman R411 Dynograph. Umbilical vascular resistance was calculated as the difference between umbilical arterial and venous pressures divided by umbilical blood flow. Blood gases and pH were measured at 39” C with Radiometer electrodes. Hemoglobin was measured spectrophotometrically as cyanmethemoglobin and hematocrit was determined by a microcentrifuge. The oxygen content was measured by a technique which requires the measurement of oxygen tension after release of the oxygen attached to hemoglobin with a deoxygenated solution containing carbon monoxide.5 The blood sample required for this is approximately 25 ~1. The accuracy of this technique was attested to by an almost exact correlation of values obtained on the same blood with the Van Slyke manometric apparatus. The correlation coefficient was 0.999, and all values agreed within 0.2 ml/l00 ml (n = 24). Saturation of hemoglobin with oxygen was calculated by dividing the oxygen content by the product of hemoglobin concentration and 1.34. Oxygen consumption was calculated as the product of umbilical blood flow and the umbilical venous minus the distal aortic blood oxygen content difference.
p-Adrenergic
activity
during
hypoxia
593
Antibiotics (400,000 U of penicillin and 500 mg of dihydrostreptomycin) were administered intramuscularly to the mother on the day of operation and for the first 5 days postoperatively. For the first week postoperatively penicillin (1 million units) and kanamycin (250 mg) were infused into the amniotic cavity. The seven animals were used in 13 individual studies, a mean of 6.2 days after operation (range, 2 to 13 days). There were one to four studies on any one sheep, and there was at least a P-day interval between studies on the same sheep. Before the study began the sheep was placed in the holding pen for several hours, and the laboratory was kept quiet. Catheters and electrodes were attached to the recorder. A plastic bag with a high flow of room air (greater than 22 L/min) passing through it was placed over the head of the sheep. In a preliminary study, 10 sets of determinations of cardiorespiratory measurements were made before the plastic bag was placed over the head of the sheep and it was shown that these values did not differ significantly. Hence, the control measurements were those with the plastic bag already in place. After the control sampling and measurements, a hypoxic gas mixture was substituted for room air without manipulation of the sheep. The hypoxic gas mixtures were made by channeling nitrogen and room air plus 5% carbon dioxide through a Y tube at flow rates above 22 L/min. The degree of hypoxia was adjusted to achieve a mean maternal arterial blood oxygen tension of 30 to 35 mm Hg. Samples were drawn at an average of 37 ? 9 (SD) min after the hypoxia was begun (range, 22 to 53 minutes), as this time range had been shown previously as giving values representative of stable conditions.6 Seven minutes after this sampling, propranolol (1 mg/kg of estimated fetal weight) was injected as a bolus into the umbilical vein or fetal inferior vena cava. After final estimation or measurement of fetal weight, it was found that the actual dosage was 1.14 mg/kg of fetal weight. Total /3-adrenergic blockade had been demonstrated previously with this dosage,i and we confirmed this total blockade by demonstrating the absence of any response to intravenous isoproterenol (0.1 mgikg of fetal weight) and the absence of any response to further bolus injections of intravenous propranolol up to 10 minutes after the first bolus. Sampling for the “propranolol” period occurred an average of 4.5 + 2 minutes (range, 1 to 7 minutes) after injection of the drug. An average of 9 2 3 minutes after this sampling, atropine, 200 pglkg of estimated fetal weight, was injected intravenously, and sampling was again carried out at 5.0 + 2.5 minutes afterward. This dosage had previously been shown to produce complete parasympathetic blockade. ‘3 7 The ewe was then allowed to breathe room air, and a further set of samples and
594
Parer
Table
November Am. J. Obstet.
I. Maternal
arterial
features
during
hypoxia,
propranolol,
Control
content (ml O,/lOO ml)
Oxygen Oxygen
saturation
6.5 _’ 1.3
L-p 91 2 6
pressure
(mm
98.5
Hg)
dioxide pressure
Base excess (mEq/L) Mean arterial blood pressure (mm Hg) Heart rate (bpm)
-c 6.2
sheep;
Oxygen content (ml O,/lOO Umbilical venous arterial
saturation
(%)
Oxygen pressure (mm Umbilical venous Umbilical
532
11
54 I? 14
2 4.7
31.6
rt 5.2
32.4
2 6.3
_’ 8.8 25.1 p < 0.01 d 7.48 i- 0.05 7.58 -p < 0.001+0.3 + 5.0 + 1.4 85 2 10 81 -p
2 2.9
25.5
k 4.2
24.0
2 4.0
2 0.07
7.56
k 0.06
7.57
?I 0.07
-
2 4.0 k 8
+0.3 + 3.9 81 f 9
-+ 35
126 + 27
-p < O.OlA
-p
0 + 2.9 802 10 115 2 21
< 0.001-
and atropine
on umbilical
venous and distal aortic blood
gases of the
Hypoxia and propranolol
Hypoxia plus propranolol plus atropine
3.5 zk 0.6
3.8 _) 1.0
3.3 2 0.9
1.9 + 0.8
2.1 4 0.7
1.9 + 1.1
28 2 10
31 2 12
27 5 10
15 t 6
17 t
16 -c 9
Hypoxia
ml) 9.4 2 1.2* L-p 6.0 2 1.1 L-p 73 -t 14 L-p 48 t 11 L-p
< 0.001< 0.001< 0.0019
< 0.001-
Fig)
arterial
Carbon dioxide pressure (mm Hg) Umbilical venous Umbilical
1.7
32.4
Control
Oxygen
f
13 studies.
Table II. Effects of propranolol hypoxic fetus
Umbilical
6.7
< 0.001-
-p
6.3 2 1.3
54 2 9
32.2
Hg)
Hypoxia fh.s prvprarwlol ph.5 atropine
< 0.001-
-p
Carbon (mm PH
to the fetus
< 0.001-
-p
Oxygen
administration Hypoxia +.s pmpranolol
Hypoxia
11.1 2 l.fP
(%)
and atropine
1,1983 Gynecol.
arterial
30.3 19.5
42.1 46.4
rt 4.2 -p _’ 1.0
< 0.001-
L-p
< 0.001’
t- 4.1 L-p 2 5.8 -
12.8 t- 2.5 9.2 k 2.4
33.8 < 0.001-
f
40.8
+ 4.4 -
I 7.32
2 L--p 0.08 I 2 0.07
14.1
2 2.4
-
3.8 -
p 4 0.01 -
14.1 ‘- 2.0 p < 0.02
10.2
2 2.3
9.2 2 3.0
31.6
+ 4.0
33.7
2 3.6
4,6
40.8
*
p < 0.02 39.1_ p < 0.02 T
4.1
PH Umbilical
venous
7.40
+I 0.04 p < 0.0,
Umbilical
arterial
7.38
f
0.04
-p Base excess (mEq/L) Umbilical venous
+ 1 i
3.9 -p
Umbilical
arterial
+2.0
sheep;
13 studies.
-p < 0.001t------p -7.8
< 0.001’
_’ 4.5 I--P
Seven **SD.
7.28
< 0.001-
-5.8 < 0.001-
< o.017.281+10.08p< p < 0.001 7.24 2 0.08
k 4.4 L-p t------p 2 5.9 L-p I
- ll.?
L-p < 0.001
0.0017.24
0.08 7.19
< 0.001’
k 3.2
t
0.09
- 12.3
+ 4.3
- 11.8
k 4.9
< 0.001’ < 0.001r - 10.2 k 4.2 < 0.001’ -p p < 0.001
< 0.01’
Volume Number
Table
P-Adrenergic
147 5
III.
Effects of propranolol
and atropine
on the umbilical
circulation
activity during hypoxia
and heart rate of the hypoxic Hypoxiu
Control
Hypoxia
Umbilical blood flow (ml/min/kg) Arterial blood pressure (mm Hg)
209 ‘- 58* 53 2 3 -p
< 0.001-
217 f 90 -p 60 2 6
Umbilical venous blood pressure (mm Hg) Intra-amniotic pressure (mm W Umbilical vascular resistance [mm Hg/(ml/ min/kg)] Fetal heart rate (bpm)
19 ‘- 5 -p 922
< 0.01-
0.17 2 0.05 165 i- 17 -p
prqbranolol
-p 24 f 6 923
9k3
140 lr. 28 -p
< 0.01-
fetus plus
propranolol plus atropine
Plus
173 2 73 -p 59 2 5 -p < 0.02 24 2 6
0.18 2 0.06 -p < 0.001-
Hypoxia
595
199 + 74 < 0.00163 + 6
< 0.01-
, 24 2 6 B-3
0.22 * 0.09
0.20 t 0.07
< 0.01113 f 21 < o.oolp
175 t 17 < 0.001-
Seven sheep; 13 studies. **SD. measurements was taken; these were designated “recovery” values, 60 t 17 minutes after cessation of hypoxia. The total duration of hypoxia was 68 2 11 minutes. Fetal weight was measured at delivery or death, and estimations of in utero weight were made by extrapolation of growth curves.’ Mean fetal weight was 2,627 2 413 gm. Student’s t test, either unpaired or, where appropriate, paired, was used for statistical comparison of treatments. To reduce the type 1 error, due to multiple comparisons with a single control, the level of significance was divided by the number of comparisons. The null hypothesis was rejected when P < 0.02.
Results Maternal
arterial
factors
during
hypoxia
and
fetal
During imposed hypoxia there was a decrease in oxygen tension to a mean of 32.4 mm Hg and appropriate decreases in oxygen content and saturation (Table I). Despite the added carbon dioxide in inspired air, there was a decrease in carbon dioxide tension, probably due to hypoxic hyperventilation. This gave rise to an alkalosis, which was respiratory, and little change in base excess. There was a slight, though significant, decrease in mean arterial blood pressure with hypoxia, and a marked increase in heart rate. During hypoxia and fetal administration of drugs there was relative stability of oxygen, carbon dioxide, and acid base measurements. The mean arterial blood pressure was unchanged, but there was a small decrease in heart rate (Table I). The mean maternal hematocrit in the control period administration
of propranolol
and
atropine.
was 26.9% ? 2.7%, and hemog-lobin 8.2 -+ 0.8 gm/dl. Oxygen, umbilical pranolol
carbon
dioxide,
venous and and atropine
and
concentration acid-base
distal aortic administration
was
values
in
blood during proto the hypoxic
fetus. Oxygen pressure, content, and saturation decreased during maternal hypoxia (Table II). These values were relatively stable after administration of the drugs, although there was a slight and statistically significant increase in oxygen pressure after propranolol. Carbon dioxide tension decreased in both umbilical blood samples with hypoxia, as it had in maternal arterial blood. There was a progressive acidemia noted in both umbilical venous and umbilical arterial blood, which was accompanied by a decrease in base excess. The mean fetal blood hematocrit in the control period was 32.4% 2 6.8%, and hemoglobin concentration was 9.3 + 2.0 gm/dl. Umbilical
circulation
propranolol
and
and atropine
fetal
heart
rate
administration
during to
the
The response to hypoxia-a stable umbilical blood flow, bradycardia, and increases in fetal arterial and umbilical venous pressures (Table III)was similar to observations previously reported from the laboratory.” After propranolol administration to the fetus, there was a decrease in umbilical blood flow and bradycardia, and the calculated vascular resistance increased. There was no change in umbilical vessel blood pressure (Table III). After atropine administration, heart rate returned to the above control values, and there was an increase in arterial blood pressure.
hypoxic
Oxygen atropine
fetus.
consumption administration
following to the
hypoxic
propranolol
and
fetus.
During
596
Tabie
Parer
IV. Effects of propranolol
November Am. J. Obstet.
and atropine
on oxygenation
of the hypoxic
fetus Hypoxia
Umbilical blood flow (ml/min/kg) Umbilical venous-arterial oxygen difference (ml O,/lOO ml) Oxygen consumption (ml/minlkg)
209 ” 5s*
217 * 90 L-p
3.3 2 0.9
5.9 2 1.3 -p
1.5 -c 0.7
Hypoxia plus propranolol ph.5 a&opine
Plm
Hypoxia
Control
1, 1983 Gynecol.
propranolol
173 * 73 <
199 + 74 < 0.001-
o.ol--~~p . +
.
1.4 f
0.7
2.4 f
1.4
p < 0.0013.0 2 1.5
2.6 2 1.3
< 0.01-
Seven sheep; 13 studies. **SD.
hypoxia, fetal oxygen consumption decreased to 51% of the control value, because of a narrowing of the venous-arterial oxygen concentration difference. After propranolol administration, there was no significant change in fetal oxygen consumption, despite a 20% drop in umbilical blood flow. After the addition of atropine, there was an increase in umbilical blood flow toward normal but, again, no significant change in oxygen consumption. Comment In the fetus, the major change in the umbilical blood gases occurred in response to hypoxia with relatively smaller changes thereafter (Tables II and IV). The pH and base excess, however, showed a progressive decline, almost certainly as a result of the metabolic acidosis. which was due to the continued duration of hypoxia, as had been described previously.” The interpretation of drug effects must, therefore, be made with due regard to these progressive changes, and the present results can be compared to previous studies of the same fetal preparation without any drug treatment.” The major maternal changes seen were those directly attributable to hypoxia. The changes in maternal heart rate were progressive and most likely due to the continued duration of hypoxia rather than to the drugs. The most striking effect of propranolol is on fetal heart rate and umbilical blood flow, where there were decreases of 1557, and 2070, respectively. In the normoxie sheep fetus we had demonstrated that proprano101 caused only a 6%) drop in heart rate and a 13%) decrease in umbilical blood flo~.~ This implies that during hypoxia there is an increase in P-adrenergic activity, which results in a tendency to maintain fetal heart rate and umbilical blood flow. The umbilical blood flow could be maintained because of /3-adrenergic vasodilatation of the placental vascular bed or by the inotropic action of sympathetic activity in maintaining cardiac output. In support of this, Cohn and associates” have shown that, under hypoxic conditions more severe than those reported here (judging by distal aortic oxy-
gen tension), p-adrenergic activity assists in maintaining the cardiac output and umbilical blood flow. By comparison with our results’ and those of Oakes and associates,” this activity is greater than that found during normoxia. In the present study, fetal oxygen consumption did not decrease significantly after p-adrenergic blockade. It is not known if this would be so under more severe degrees of hypoxia, such as that reported by Cohn and associates,‘” where umbilical blood flow decreased by approximately 30%. Under such conditions, it is likely that the venous-arterial oxygen concentration difference cannot widen further, so fetal oxygen consumption would decrease.6 By adding parasympathetic blockade to P-adrenergic blockade, we have been able to observe the combined effects of these branches of the autonomic nervous system in maintenance of fetal oxygenation during hypoxia. The parasympathetic contribution to maintenance of oxygenation under these conditions is minimal but its role in decreasing heart rate may be more important. This could conceivably contribute to the fetal adaptation to hypoxia by limiting myocardial work and oxygen consumption,’ thus prolonging the duration of tolerance by the fetus to a given degree of hypoxia. Myocardial blood flow is increased in the absence of vagal activity in the fetus subjected to mild or severe hypoxia,12 so the vagal activity can be considered to be contributing to the minimizing of myocardial work. It is of interest that the net fetal heart rate is slightly elevated above normal in the presence of parasympathetic and P-adrenergic blockade in the normoxic fetus,H and the same is true in the hypoxic fetus (Table III). This suggests that the baseline heart rate consists solely of the net result of these two influences. The clinical use of propranolol for maternal indications has had both support and criticism. In the past it has been difficult to separate out fetal effects due to the antecedent maternal illness requiring drug treatment and the direct effects of the drug itself.13 Most recent authorities agree with its use in moderate doses when
Volume Number
147 5
p-Adrenergic
indicated,i4 demonstrate
and its
mothers.is the doses
that
present
study
possible
producing
is clear tive thus
The
maximum
there have been published efficacy in hypertensive
total
blockade
propranolol
effects of decreasing
is of help
acute
in the
removes
P-adrenergic the degree
effects
trials pregnant
to
in determining of
the
hypoxic
some
of the
drug, fetus.
at It
protec-
activity during asphyxia, of “reserve” of the fetus.
REFERENCES
activity
during
Bound
volumes
available
to subscribers
Bound volumes of the AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY are available to subscribers (only) for the 1983 issues from the Publisher, at a cost of $70.95 ($90.00 international) for Vol. 145 (January-April), Vol. 146 (May-August), and Vol. 147 (September-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the JOURNAL name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mr. Deans Lynch at The C. V. Mosby Company, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA.
Subscriptions must be in force to qualify. a regular JOURNAL subscription.
597
7. Vapaavouri, E. K., Shinebourne, E. A., Williams, R. L., Heymann, M. A., and Rudolph, A. M.: Development of cardiovascular responses to autonomic blockade in intact fetal and neonatal lambs, Biol. Neonate 22: 177, 1973. 8. Winters, L. M., and Feuffel, G.: Studies on the physiology of reproduction in the sheep. IV. Fetal development, University of Minnesota Agriculture Experiment Station Technical Bulletin, Minneapolis, 1936, University of Minnesota, pp. 118. 9. Harris, J. L., Krueger, T. R., and Parer, J. T.: The effect of parasympathetic and /3-adrenergic blockade on the umbilical circulation in the unanesthetized fetal sheep,L Gynecol. Obstet. Invest. lOt306, 1979. 10. Cohn. H. E.. Piasecki. G. I.. and Iackson. B. T.: The effect of /3-adrenergic stimula~o’n on fetal cardiovascular function during hypoxemia, AM. J. OBSTET. GYNECOL. 144~810, 1982. 11. Oakes, G. K., Walker, A. M., Ehrenkranz, R. A., and Chez, R. A.: Effect of propranolol infusion on the umbilical and uterine circulations of pregnant sheep, AM. J. OBSTET. GYNECOL. 126:1038, 1976. 12. Cohn, H. E., Piasecki, G. J., and Jackson, B. T.: The effect of fetal heart rate on cardiovascular function during hypoxemia, AM. J. OBSTET. GYNECOL. 13&l 190, 1980. 13. Datta, S., Kitzmiller, J. L., Ostheimer, G. W., and Schoenbaum, S. C.: Propranolol and parturition, Obstet. Gynecol. 51:577, 1978. 14. Rubin, P. C.: Beta-blockers in pregnancy, N. Engl. J. Med. 305:1323, 1981. 15. Gallery, E. D. M., Saunders, D. M., Hunyor, S. N., and Gyory, A. Z.: Randomized comparison of methyldopa and oxprenolol for treatment of hypertension in pregnancy, Br. Med. J. 1:1591, 1979. .A
1. Parer, J. T.: The effect of atropine on heart rate and oxygen consumption of the hypoxic fetus. Submitted for publication. 2. Reuss, M. L., Parer, J. T., Harris, J. L., and Krueger, T. R.: Hemodynamic effects of alpha-adrenergic blockade during hypoxia in fetal sheep, AM. J. OBSTET. GYNECOL. 142:410, 1982. 3. Young, W. P., Greasy, R. K., and Rudolph, A. M.: Catheterization of the common umbilical vein for chronic fetal lamb studies, J. Appl. Physiol. 37:620, 1974. 4. Berman, W., Goodlin, R. C., Heymann, M. A., and Rudolph, A. M.: Measurement of umbilical blood flow in fetal lambs in utero, J. Appl. Physiol. 39:1056, 1975. 5. Duke, G. S., and Newhouse, Y.: Micromethod for measuring blood oxygen content by determining oxygen tension after saturation with carbon monoxide, Am. Rev. Respir. Dis. 110:814, 1974. 6. Parer, J. T.: The effect of acute maternal hypoxia on fetal oxygenation and the umbilical circulation in the sheep, Eur. J. Obstet. Gynecol. Reprod. Biol. 10:125, 1980.
hypoxia
Bound
volumes
are not available
in place of