The Clearance of ACTH from the Plasma of Adult and Fetal Sheep C. T. JONES, E. LUTHER,* J. W. K. RITCHIE, AND D. WORTHINGTON**
Nuffield Institute for Medical Research, University of Oxford, Headley Way, Oxford 0X3 9DS, England ABSTRACT. The disappearance of 125I-ACTH from the circulation of 4 pregnant and fetal sheep has been followed after a single injection to the ewe or fetus. The mean metabolic clearance rate for the fetus and the ewe was 55 and 34 ml/min/kg respectively, giving a half-life in each case of about
1 min. The higher fetal than maternal arterial plasma ACTH concentration has been ascribed to a higher rate of secretion rather than a reduced rate of clearance compared with the ewe. There was no evidence of placental transfer of immunologically reactive ACTH. (Endocrinology 96: 231, 1975).
min and 2, 4, 8, and 13-14 hr after the injection 4 ml blood samples were taken via the fetal and maternal carotid catheters and centrifuged for 2 min at 1500 x g and 2 C to separate the plasma. The 125I-ACTH was extracted from plasma as described by Rees et al. (10) for ACTH and the counts obtained corrected for recovery (125I-ACTH recovery from 50 mg Corning 7930 glass was 68.4 ± 3.2% (8)). Immunoprecipitable counts were determined after incubation with ACTH antibody for 4 days at 4 C and estimation of unbound radioactivity as described by Rees et al. (10). Under the conditions of the incubation, with 125I-ACTH in the concentration range 20-1000 pg, 88.4 ± 2.4% (average of 6 determinations) of the 125I-ACTH binds to antibody. The ACTH antibody used, which crossreacts with the species-specific N-terminal portion of the ACTH molecule, was raised in rabbits against ACTHi_24 (Synacthen, CIBA Laboratories, Horsham, U.K.). Immunoassay results show good correlation with biological activity. The ACTH used for iodination was the porcine 3rd International Working Standard (National Institute for Medical Research, London, U.K.). The preparation of 125I-ACTH was carried out with peroxidase: 10 fx\ 0.5M sodium phosphate, pH 7.5; 50 Materials and Methods fi\ 50 mM sodium phosphate, pH 7.5; 1 /xg lac125 Four pregnant sheep of mixed breeds were im- toperoxidase (Sigma); 10 fjd 1 mM H2O2; 10 /nl Na I (1 mCi, Radiochemical Centre, Amersham, U.K.) and planted with fetal and maternal carotid and jugular catheters and arterial blood was collected for blood incubated at room temperature (20 C) for 1 min. The gas analysis as described by Dawes et al. (8). At least reaction was stopped with 20 (xg sodium metabisul10 days had elapsed after the implantation of cathe- phite. This was found to give a more homogeneous ters before the experiment was carried out. On day 1 preparation by electrophoresis (Fig. 1) than that given the fetuses were injected into the jugular vein with 10 by the chloramine-T method125of Greenwood et al. (9). /xCi I25I-ACTH (ca. 200 /u.Ci//xg) in 1 ml. 0.9% NaCl. After radioiodination the I-ACTH was adsorbed On day 2 maternal injections of 70 /tCi 125I-ACTH (ca. onto Quso (G 32, Philadelphia Quartz Co.) from which 200 /t*Ci//i,g) in 2 ml. 0.9% NaCl were given through it was eluted with 2 ml. 40% acetone containing 1% the jugular catheter. At 0.5, 1, 2, 4, 10, 20, 40 and 60 acet'.c acid. Corticosteroids were determined on plasma samples, after washing plasma with 3 ml petroleum spirit Received March 13, 1974. (40-60 C), by the method of Murphy (11) as described * Pressent address: Department of Obstetrics and by Bassett and Hinks (12). The steroids measured in Gynecology, Memorial University of Newfoundland, plasma were predominantly cortisol and corticosterone (unpublished observations). St. John's, Newfoundland, Canada. ** Department of Obstetrics and Gynecology, Where appropriate, results are expressed as Queens University Kingston, Ontario, Canada. means ± SD.
T
HE role played by the fetal pituitary and adrenal in the initiation of parturition has been reviewed in detail by Liggins (1). Observations in numerous species showing a large rise in plasma corticosteroids prior to parturition (2-6) have suggested that ACTH may be one of the hormonal factors responsible for the initiation of birth. The rise in fetal plasma corticosteroids may be preceded by a rise in the concentration of fetal plasma ACTH. Recently we have observed that the arterial blood concentration of ACTH at rest and during periods of hypoxia is higher in fetal than maternal sheep and that the fetal adrenal appears to be relatively unresponsive to these comparatively high fetal ACTH concentrations (7). To determine if the higher fetal plasma ACTH concentration is the result of increased secretion, reduced clearance or both we have followed the disappearance of 125I-ACTH from the fetal and maternal circulation of sheep.
231
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125
Results
|-ACTH
(a) ch loramine T
•z
Endo • 1975 Vol 96 • No 1
NOTES AND COMMENTS
232
16
-
10 cathode
anode
distance from origin, cm
FIG. 1. Electrophoresis (Cellulose Acetate; 0.5M tris, 0.021M EDTA, 0.075M-H 3 BO 3 ) pH 9.3; 100 V/cm; ca. 5
ma/cm; - 5 C; 2 hr) of 125I-ACTH prepared by (a) chloramine-T method, (b) peroxidase method. The iodinated peptide used was that obtained after prior purification with Quso G32 glass. TABLE
The pregnant ewes and their fetuses were normal before the injection of 12SI-ACTH as judged by their arterial pH, pO2 and pCO2 (Table 1). The sheep were not in labor. Immunoprecipitable ACTH disappeared very rapidly from both the fetal and maternal circulation during the hour after the injection (Fig. 2). There was no detectable placental transfer of l25 I-ACTH after the fetal or maternal injection. The metabolic clearance rate for 125I-ACTH was determined as described by Tait and Burstein (15). For the disappearance from the maternal circulation it was 1.65-2.7 1/min and from the fetal circulation 125-370 ml/min. The clearance per unit body weight is slightly higher 55 ± 17 ml/min/kg for the fetus than the ewe 34 ± 8 ml/min/kg (p < 0.01). However, the half-life (calculated from the metabolic clearance rate assuming the disappearance obeys first order kinetics) at 1.1 ± 0.5 min and 1.03 ± 0.24 min for the fetus and ewe respectively are not significantly different (Table 1).
1. The metabolic clearance rate, half-life, and secretion rate of ACTH in the circulation of fetal and maternal sheep Sheep 1
Sheep 2 .
125
Sheep 3 143
131
Sheep 4 my
Days pregnant Fetal Wt (kg) Plasma volume (ml)*
2.7
Maternal 57
Fetal 3.8
Maternal 64
Fetal 5.3
Maternal 60
Fetal 5.0
Maternal 63
200
3,000
350
3,000
400
3,000
390
3,000
46
29
35
27
70
45
70
38
Plasma ACTH (Pg/ml)$
112
54
169
63
74
21
53
23
Secretion rate (pg/min/kg)t
5,152
1,566
5,915
1,701
5,170
945
3,470
770
Metabolic clearance rate (ml/inin/kg)**
Half-life (min)ff
1.16
1.26
1.82
1.2
Plasma glucocorticoid (ng/ml)
8.9
4.2
7.6
9.5
12.1
7.2
pH
7.37
7.49
7.32
7.47
7.3
7.44
0.75
0.77
0.76
14.3 7.31
0.9
8.5 7.51
pO, (mm Hg)
23
95
27
103
24
98
26
99
pCO, (mm Hg)
46
35
49
32
44
33
47
36
Packed cell volume (%)
29
26
29
27
28
25
26
28
* Estimated from the data of Broughton-Pipkin and Kirkpatrick (13) and Christopherson and Webster (14). ** Metabolic clearance rate (MCR) was calculated from MCR = l//xdt where x is the fraction of the total injection remaining/nil at time, t (15). § Each ACTH concentration is the mean of 6 determinations made during the course of the experiment. The maximum coefficient of variation was 28%. t Secretion rate = ACTH concentration x MCR. tt Calculated from the plasma volume (V) and the MCR, where half-life = V Iogj2/MCR (assuming ACTH decay obeys first order kinetics).
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233
NOTES AND COMMENTS The plasma ACTH concentration in fetal sheep was 2-3 times higher than maternal. Thus, the ACTH secretion rate for the fetus (4921 ± 1032 pg/min/kg) was significantly higher than maternal (1245 ± 457 pg/min/kg; p < 0.001).
10 "4 r-
10 -5
Discussion fetal
Nonpregnant sheep with chronically implanted carotid catheters have arterial plasma 10 ACTH concentrations in the range 10-60 pg/ml (unpublished observations), similar to those found in the maternal circulation in the present experiments. The calculated half-life of ACTH in the fetal 10 circulation is comparable to that recently determined for Synacthen during infusion into fetal sheep (unpublished observations). It may be an underestimate of the rate of ACTH 8 clearance since a steady state distribution is not 10" L L 10 14 immediately achieved after a single injection. Comparable, though slower, rates of disappeartime, hr ance have been observed in rats (16-19). Little information is available on the mechanism of FIG. 2. The disappearance of immunologically reacclearance of ACTH, although the kidney is tive 125I-ACTH after a single injection into ewe no. 3 probably an important site of clearance in adults (o) or its fetus (•). (19-23). However, as about 2% of the cardiac output of the fetal sheep goes to the kidney (24), There have been suggestions that the placenta its contribution to ACTH clearance is likely to of the rat is permeable to ACTH (33-35). be small. Since the clearance from the fetal However, recent work has suggested that this is circulation is at least as rapid as that from the not so for the human, rhesus monkey or sheep adult and since the sheep placenta receives placenta (7,36-38). The present observations about 50% of the fetal cardiac output (24), this demonstrate that immunologically reactive suggests that either the fetal tissues are more ACTH does not cross the placenta of the sheep effective at clearing ACTH than those of the in significant quantities. adult or the placenta represents a major site of clearance. A role for the placenta in ACTH Acknowledgments clearance may explain the isolation of ACTHThis work was completed during the tenure of like material from the placenta (25). However, it Research Fellowships from the Canadian Medical is also possible that plasma is a major site for Research Council (E.L. and D.W.) and with the help ACTH degradation (26,27). of grants from the Medical Research Council and the The results suggest that higher rates of ACTH Wellcome Trust. We would like to thank Dr. G. S. secretion rather than reduced clearance are Dawes for valuable discussion and criticism and M. responsible for the higher fetal than maternal Puklavec for expert technical assistance. plasma ACTH concentration. However, it is References possible that a stimulus for ACTH secretion such as hypoxia (7) influences the normal rates 1. Liggins, G. C , R. J. Fairclough, S. A. Grieves, J. of clearance by changing the distribution of the Z. Kendall, and B. S. Knox, Recent Progr Horm cardiac output (28-32). Thus a change in the Res 29: 111, 1973. plasma ACTH concentration of the fetus may be 2. Jochle, W., Ann Rev Pharmacol 13: 33, 1973. the result of a change in the rate of secretion or 3. Bassett, J. M., and G. D. Thorburn, J Endocrinol clearance or both. 43: 449, 1969. No direct information on placental permeabil4. Comline, R. S., P. W. Nathanielsz, R. B. Paisey, ity to ACTH has previously been available. and M. Silver,/ Physiol (Lond) 210: 141P, 1970.
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234
NOTES AND COMMENTS
5. Holt, P. G., and T. Oliver, Biochem J 108: 333, 1968. 6. Mulay, S., G. Giannopoulos, and S. Soloman, Endocrinology 93: 1342, 1973. 7. Boddy, K., C. T. Jones, C. Mantell, J. G. Ratcliffe, and J. S. Robinson, Endocrinology 94: 588, 1974. 8. Dawes, G. S., H. E. Fox, B. M. Leduc, G. C. Liggins, and R. T. Richards, / Physiol (London) 220: 119, 1972. 9. Greenwood, F. C., W. M. Hunter, and J. S. Glover, Biochem J 89: 114, 1963. 10. Rees, L. H., D. M. Cook, J. W. Kendall, C. F. Allen, R. M. Kramer, J. G. Ratcliffe, and R. A. Knight, Endocrinology 89: 254, 1971. 11. Murphy, B. E. P., / Clin Endocrinol Metab 27: 973, 1967. 12. Bassett, J. M., and N. T. Hinks, / Endocrinol 44: 387, 1969. 13. Broughton Pipkin, F., and S. M. L. Kirkpatrick, Quart J Exp Physiol 58: 181, 1973. 14. Christopherson, R. J., and A. J. F. Webster, J Physiol (Lond) 221: 441, 1972. 15. Tait, J. F., and S. Burstein, In Pincus, G., K. V. Thimann, and E. B. Astwood (eds.), The Hormones, vol. V., Academic Press, New York, 1964, p. 441. 16. Greenspan, F. S., C. H. Li, and H. M. Evans, Endocrinology 46: 261, 1950. 17. Sonenberg, M., A. S. Keston, and W. L. Money, Endocrinology 48: 148, 1951. 18. Sydnor, L. K., and G. Sayers, Proc Soc Exp Biol Med 83: 729, 1953. 19. Cats, A., and A. A. H. Kassenaar, Ada Endocrinol (Kbh) 24: 35, 1957. 20. Richards, J. B., and G. Sayers, Proc Soc Exp Biol Med 77: 87, 1951. 21. Sonenberg, M., M. L. Money, A. S. Keston, P. J. Fitzgerald, and J. F. Godwin, Endocrinology 49: 709, 1951.
22. Cats, A., and A. A. H. Kassenaar, Ada Endocrinol (Kbh) 24: 43, 1957. 23. Golder, M. P., and A. R. Boyns, J Endocrinol 49: 649, 1971. 24. Rudolph, A. M., and M. A. Heymann, Circ Bes 21: 163, 1967. 25. Opsall, J. C , C. N. H. Long, and E. G. Fry, YaleJ Biol Med 23: 399, 1951. 26. Mirsky, I. A., G. Perisutti, and N. C. Davis, 7 Clin Invest 38: 14, 1959. 27. Meakin, J. W., W. H. Tingey, and D. H. Nelson, Endocrinology 66: 59, 1960. 28. Assali, N. S., L. W. Holm, and N. Sehgal, Circ Bes 11: 423, 1962. 29. Campbell, A. G. M., G. S. Dawes, A. P. Fishman, and A. I. Hyman, Circ Bes 21: 229, 1967. 30. Dawes, G. S., B. V. Lewis, J. E. Milligan, M. R. Roche, and N. S. TalnerJ Physiol (Lond) 195: 55, 1968. 31. Dawes, G. S., S. L. B. Duncan, B. V. Lewis, C. L. Merlet, J. B. Owen-Thomas, and J. T. Reeves, / Physiol (Lond) 201: 105, 1969. 32. Dunne, J. T., J. E. Milligan, and B. W. Thomas, AmJ Obstet Gynec 112: 323, 1972. 33. Jones, J. M., W. L. Lloyd, and T. C. Wyatt, Endocrinology 53: 182, 1953. 34. Knobil, E., and F. N. Biggs, Fed Proc 13: 80, 1954. 35. , and , Endocrinology 57: 147, 1955. 36. Alexander, D. P., H. G. Britton, M. L. Forsling, D. A. Nixon, and J. G. Ratcliffe. In Pierrepoint, C. G. (ed.), The Endocrinology of Pregnancy and Parturition—Experimental Studies in the Sheep, Alpha Omega Alpha Publishing, Cardiff, 1973, p. 112. 37. Kittinger, G. W., N. B. Beamer, F. Hagemenas, J. D. Hill, W. L. Baughman, and A. J. Ochsner, Endocrinology 91: 1037, 1972. 38. Allen, J. P., D. M. Cook, J. W. Kendall, and R. McGilvraJ Clin Endocrinol Metab 37: 230, 1973.
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Nuffield Institute for Medical Research, University of Oxford, Headley Way, Oxford 0X3 9DS, England ABSTRACT. The disappearance of 125I-ACTH from the circulation of 4 pregnant and fetal sheep has been followed after a single injection to the ewe or fetus. The mean metabolic clearance rate for the fetus and the ewe was 55 and 34 ml/min/kg respectively, giving a half-life in each case of about
1 min. The higher fetal than maternal arterial plasma ACTH concentration has been ascribed to a higher rate of secretion rather than a reduced rate of clearance compared with the ewe. There was no evidence of placental transfer of immunologically reactive ACTH. (Endocrinology 96: 231, 1975).
min and 2, 4, 8, and 13-14 hr after the injection 4 ml blood samples were taken via the fetal and maternal carotid catheters and centrifuged for 2 min at 1500 x g and 2 C to separate the plasma. The 125I-ACTH was extracted from plasma as described by Rees et al. (10) for ACTH and the counts obtained corrected for recovery (125I-ACTH recovery from 50 mg Corning 7930 glass was 68.4 ± 3.2% (8)). Immunoprecipitable counts were determined after incubation with ACTH antibody for 4 days at 4 C and estimation of unbound radioactivity as described by Rees et al. (10). Under the conditions of the incubation, with 125I-ACTH in the concentration range 20-1000 pg, 88.4 ± 2.4% (average of 6 determinations) of the 125I-ACTH binds to antibody. The ACTH antibody used, which crossreacts with the species-specific N-terminal portion of the ACTH molecule, was raised in rabbits against ACTHi_24 (Synacthen, CIBA Laboratories, Horsham, U.K.). Immunoassay results show good correlation with biological activity. The ACTH used for iodination was the porcine 3rd International Working Standard (National Institute for Medical Research, London, U.K.). The preparation of 125I-ACTH was carried out with peroxidase: 10 fx\ 0.5M sodium phosphate, pH 7.5; 50 Materials and Methods fi\ 50 mM sodium phosphate, pH 7.5; 1 /xg lac125 Four pregnant sheep of mixed breeds were im- toperoxidase (Sigma); 10 fjd 1 mM H2O2; 10 /nl Na I (1 mCi, Radiochemical Centre, Amersham, U.K.) and planted with fetal and maternal carotid and jugular catheters and arterial blood was collected for blood incubated at room temperature (20 C) for 1 min. The gas analysis as described by Dawes et al. (8). At least reaction was stopped with 20 (xg sodium metabisul10 days had elapsed after the implantation of cathe- phite. This was found to give a more homogeneous ters before the experiment was carried out. On day 1 preparation by electrophoresis (Fig. 1) than that given the fetuses were injected into the jugular vein with 10 by the chloramine-T method125of Greenwood et al. (9). /xCi I25I-ACTH (ca. 200 /u.Ci//xg) in 1 ml. 0.9% NaCl. After radioiodination the I-ACTH was adsorbed On day 2 maternal injections of 70 /tCi 125I-ACTH (ca. onto Quso (G 32, Philadelphia Quartz Co.) from which 200 /t*Ci//i,g) in 2 ml. 0.9% NaCl were given through it was eluted with 2 ml. 40% acetone containing 1% the jugular catheter. At 0.5, 1, 2, 4, 10, 20, 40 and 60 acet'.c acid. Corticosteroids were determined on plasma samples, after washing plasma with 3 ml petroleum spirit Received March 13, 1974. (40-60 C), by the method of Murphy (11) as described * Pressent address: Department of Obstetrics and by Bassett and Hinks (12). The steroids measured in Gynecology, Memorial University of Newfoundland, plasma were predominantly cortisol and corticosterone (unpublished observations). St. John's, Newfoundland, Canada. ** Department of Obstetrics and Gynecology, Where appropriate, results are expressed as Queens University Kingston, Ontario, Canada. means ± SD.
T
HE role played by the fetal pituitary and adrenal in the initiation of parturition has been reviewed in detail by Liggins (1). Observations in numerous species showing a large rise in plasma corticosteroids prior to parturition (2-6) have suggested that ACTH may be one of the hormonal factors responsible for the initiation of birth. The rise in fetal plasma corticosteroids may be preceded by a rise in the concentration of fetal plasma ACTH. Recently we have observed that the arterial blood concentration of ACTH at rest and during periods of hypoxia is higher in fetal than maternal sheep and that the fetal adrenal appears to be relatively unresponsive to these comparatively high fetal ACTH concentrations (7). To determine if the higher fetal plasma ACTH concentration is the result of increased secretion, reduced clearance or both we have followed the disappearance of 125I-ACTH from the fetal and maternal circulation of sheep.
231
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125
Results
|-ACTH
(a) ch loramine T
•z
Endo • 1975 Vol 96 • No 1
NOTES AND COMMENTS
232
16
-
10 cathode
anode
distance from origin, cm
FIG. 1. Electrophoresis (Cellulose Acetate; 0.5M tris, 0.021M EDTA, 0.075M-H 3 BO 3 ) pH 9.3; 100 V/cm; ca. 5
ma/cm; - 5 C; 2 hr) of 125I-ACTH prepared by (a) chloramine-T method, (b) peroxidase method. The iodinated peptide used was that obtained after prior purification with Quso G32 glass. TABLE
The pregnant ewes and their fetuses were normal before the injection of 12SI-ACTH as judged by their arterial pH, pO2 and pCO2 (Table 1). The sheep were not in labor. Immunoprecipitable ACTH disappeared very rapidly from both the fetal and maternal circulation during the hour after the injection (Fig. 2). There was no detectable placental transfer of l25 I-ACTH after the fetal or maternal injection. The metabolic clearance rate for 125I-ACTH was determined as described by Tait and Burstein (15). For the disappearance from the maternal circulation it was 1.65-2.7 1/min and from the fetal circulation 125-370 ml/min. The clearance per unit body weight is slightly higher 55 ± 17 ml/min/kg for the fetus than the ewe 34 ± 8 ml/min/kg (p < 0.01). However, the half-life (calculated from the metabolic clearance rate assuming the disappearance obeys first order kinetics) at 1.1 ± 0.5 min and 1.03 ± 0.24 min for the fetus and ewe respectively are not significantly different (Table 1).
1. The metabolic clearance rate, half-life, and secretion rate of ACTH in the circulation of fetal and maternal sheep Sheep 1
Sheep 2 .
125
Sheep 3 143
131
Sheep 4 my
Days pregnant Fetal Wt (kg) Plasma volume (ml)*
2.7
Maternal 57
Fetal 3.8
Maternal 64
Fetal 5.3
Maternal 60
Fetal 5.0
Maternal 63
200
3,000
350
3,000
400
3,000
390
3,000
46
29
35
27
70
45
70
38
Plasma ACTH (Pg/ml)$
112
54
169
63
74
21
53
23
Secretion rate (pg/min/kg)t
5,152
1,566
5,915
1,701
5,170
945
3,470
770
Metabolic clearance rate (ml/inin/kg)**
Half-life (min)ff
1.16
1.26
1.82
1.2
Plasma glucocorticoid (ng/ml)
8.9
4.2
7.6
9.5
12.1
7.2
pH
7.37
7.49
7.32
7.47
7.3
7.44
0.75
0.77
0.76
14.3 7.31
0.9
8.5 7.51
pO, (mm Hg)
23
95
27
103
24
98
26
99
pCO, (mm Hg)
46
35
49
32
44
33
47
36
Packed cell volume (%)
29
26
29
27
28
25
26
28
* Estimated from the data of Broughton-Pipkin and Kirkpatrick (13) and Christopherson and Webster (14). ** Metabolic clearance rate (MCR) was calculated from MCR = l//xdt where x is the fraction of the total injection remaining/nil at time, t (15). § Each ACTH concentration is the mean of 6 determinations made during the course of the experiment. The maximum coefficient of variation was 28%. t Secretion rate = ACTH concentration x MCR. tt Calculated from the plasma volume (V) and the MCR, where half-life = V Iogj2/MCR (assuming ACTH decay obeys first order kinetics).
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233
NOTES AND COMMENTS The plasma ACTH concentration in fetal sheep was 2-3 times higher than maternal. Thus, the ACTH secretion rate for the fetus (4921 ± 1032 pg/min/kg) was significantly higher than maternal (1245 ± 457 pg/min/kg; p < 0.001).
10 "4 r-
10 -5
Discussion fetal
Nonpregnant sheep with chronically implanted carotid catheters have arterial plasma 10 ACTH concentrations in the range 10-60 pg/ml (unpublished observations), similar to those found in the maternal circulation in the present experiments. The calculated half-life of ACTH in the fetal 10 circulation is comparable to that recently determined for Synacthen during infusion into fetal sheep (unpublished observations). It may be an underestimate of the rate of ACTH 8 clearance since a steady state distribution is not 10" L L 10 14 immediately achieved after a single injection. Comparable, though slower, rates of disappeartime, hr ance have been observed in rats (16-19). Little information is available on the mechanism of FIG. 2. The disappearance of immunologically reacclearance of ACTH, although the kidney is tive 125I-ACTH after a single injection into ewe no. 3 probably an important site of clearance in adults (o) or its fetus (•). (19-23). However, as about 2% of the cardiac output of the fetal sheep goes to the kidney (24), There have been suggestions that the placenta its contribution to ACTH clearance is likely to of the rat is permeable to ACTH (33-35). be small. Since the clearance from the fetal However, recent work has suggested that this is circulation is at least as rapid as that from the not so for the human, rhesus monkey or sheep adult and since the sheep placenta receives placenta (7,36-38). The present observations about 50% of the fetal cardiac output (24), this demonstrate that immunologically reactive suggests that either the fetal tissues are more ACTH does not cross the placenta of the sheep effective at clearing ACTH than those of the in significant quantities. adult or the placenta represents a major site of clearance. A role for the placenta in ACTH Acknowledgments clearance may explain the isolation of ACTHThis work was completed during the tenure of like material from the placenta (25). However, it Research Fellowships from the Canadian Medical is also possible that plasma is a major site for Research Council (E.L. and D.W.) and with the help ACTH degradation (26,27). of grants from the Medical Research Council and the The results suggest that higher rates of ACTH Wellcome Trust. We would like to thank Dr. G. S. secretion rather than reduced clearance are Dawes for valuable discussion and criticism and M. responsible for the higher fetal than maternal Puklavec for expert technical assistance. plasma ACTH concentration. However, it is References possible that a stimulus for ACTH secretion such as hypoxia (7) influences the normal rates 1. Liggins, G. C , R. J. Fairclough, S. A. Grieves, J. of clearance by changing the distribution of the Z. Kendall, and B. S. Knox, Recent Progr Horm cardiac output (28-32). Thus a change in the Res 29: 111, 1973. plasma ACTH concentration of the fetus may be 2. Jochle, W., Ann Rev Pharmacol 13: 33, 1973. the result of a change in the rate of secretion or 3. Bassett, J. M., and G. D. Thorburn, J Endocrinol clearance or both. 43: 449, 1969. No direct information on placental permeabil4. Comline, R. S., P. W. Nathanielsz, R. B. Paisey, ity to ACTH has previously been available. and M. Silver,/ Physiol (Lond) 210: 141P, 1970.
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234
NOTES AND COMMENTS
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