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Stimulation of ACTH secretion by indomethacin and reversal by exogenous prostaglandins
PROSTAGLANDINS
STIMULATION OF ACTH SECRETION BY INDOMETHACIN AND REVERSAL BY EXOGENOUS PROSTAGLANDINSl
G.A. Hedge2
Department of Physiology Arizona Health Science Center University of Arizona Tucson, Arizona
85724
ABSTRACT
The prostaglandin (PG) synthesis inhibitor, indomethacin, has been found to enhance adrenocorticotropin (ACTH) secretion upon injection directly into the anterior pituitary at a dose that is ineffective intravenously. Such stimulation was observed in combination with, and in the absence of, stimulation by a corticotropin-releasingfactor (CRF) preparation. It was reversed to varying degrees by replacing certain PGs exogenously. It is suggested that endogenous PGs in the anterior pituitary participate in the modulation of the sensitivity of this gland to the hypothalamic neurohormone, CRF.
ACKNOWLEDGEMENT
The technical assistance of Ms. Dona Clark and Ms. Nancy Hernden is gratefully acknowledged.
1These studies were supported by USPHS Research Grant AM 13794. 2 Present address: Department of Physiology, West Virginia Medical Center, Morgantown, West Virginia
JULY 1977 VOL. 14 NO. 1
26506
145
PROSTAGLANDINS
INTRODUCTION
It is now recognized that the prostaglandins (PG) can affect the function of the hypothalamo-pituitary-adrenalaxis at multiple sites (1). The most striking, and the most well documented, of these effects is the stimulatory effect of exogenous PGs exerted at the level of the hypothalamus (2, 3, 4). Although studies such as these suggested that the PGs had no effect at the level of the anterior pituitary, subsequent work has shown that'the PGs can indeed alter ACTR secretion by acting at this level (5). In contrast to the hypothalamic effect, this pituitary effect is inhibitory in nature and it is of relatively low magnitude. Although it seems quite clear that the PGs can suppress pituitary responsiveness to a CRF preparation, it is not known whether this effect is of physiological importance. The possibility that this is simply a pharmacological effect, completely unrelated to endogenous PGs, must certainly be considered. The present experiments attempt to make this distinction by studying both basal and CRF-stimulatedACTH secretion after blocking the synthesis of endogenous PGs with the drug indomethacin (Id). In addition, we have attempted to reverse the effects of Ind by providing PGs exogenously.
MATERIALS
ANDMETHODS
Female Sprague-Dawley rats from our own breeding colony (started from Charles River CD rats) weighing 180-230 grams were used throughout these experiments. The animals were fed Purina Rat Chow and given tap water ad libitum. They were housed in temperature and humidity controlled quzxh a cycle of 12 hours of light and 12 hours of dark. In order to circumvent the extra-pituitary effects of the PGs or Ind, these substances were injected stereotaxically directly into the anterior pituitary in all of these experiments. This was accomplished under pentobarbital anesthesia (4.5 mg/lOO g body weight) by a technique that has been described in detail elsewhere (6, 7). In brief, a small (200-300 u o.d.) glass cannula was stereotaxicallyplaced into the anterior pituitary from the dorsal aspect. The rate of injection was always 2 ~1 per min., and each injection was followed with a similar injection of toluidine blue dye to assist in the assessment of the extent of the distribution of the test material. Injection volumes and doses were as follows: CRF, 0.02 median eminence equivalents in 1 ~1; Ind, 50 ug in 5 ~1; PG, 2 pg in 2 ~1. All rats were pre-treated with dexamethasone (25 ug/lOO g body wt., subcutaneously) 3-6 hours prior to injection in order to prevent the ACTH secretion that would normally be evoked by the stereotsxic procedure. In the one case in which Ind was injected intravenously as a control, the substance was diluted to 0.5 ml with physiological saline and then injected into a lateral tail vein. The PGs used in these experiments were a gift from Dr. John E. Pike, Upjohn Company, Kalamazoo, Michigan. They were prepared by dissolving them in 95% ethanol and then adding nine parts 0.02% NaC03 to one part
JULY 1977 VOL. 14 NO. 1
PROSTAGLANDINS
of the ethanol. Aliquots of the stock solutions adequate for one day's work were capped under nitrogen and stored refrigerated. The hypothalamic extract used ss a CRF was kindly provided by the NIAMDD Hormone Distribution Program. This lyophilized preparation was reconstituted with water, aliquoted, and stored frozen (-2OC) until use, at which time, it was diluted with saline so that 1 ul contained 0.02 median eminence equivalents. Ind was dissolved in 0.1 M NaPOh buffer as described by Armstrong and Grinwich (8). All substances to be microinjected had pH values that lay between 6.0 and 7.8. Fifteen minutes after the beginning of the injection of the Ind (or buffer control), the rats were decapitated and trunk blood was collected. Plasma was stored frozen until fluorometric assay for corticosterone as et al an index of ACTH secretion. The method used was that of Glick --3 (9) with minor modification (10). All data are presented as means accompanied by their standard errors. The number of rats comprising each group is indicated on the histogram bars. Student's t-test (Fig. 1) and Dunnett's multiple comparison test (Fig. 2) were used to establish the significance of differences between groups.
RESULTS The data in Fig. 1 demonstrate the effect of Ind on ACTH secretion from unstimulated pituitaries, and from those stimulated by the CRF preparation. The dose of CRF was chosen from our previous experience (5) as one that will elicit a rather small response. In the present work, it can be seen that this dose elicits a significant (pXO.02) increase in ACTH secretion (see buffer control data on the left side of Fig. 1). Whether the pituitaries have been stimulated or not, the Ind elicits a striking increase in ACTH secretion. This cannot be due to the spread of the Ind to the adrenal since this same dose of the drug given intravenously fails to elicit any ACTH secretion (4.3 * 1.1 ug/dl).
Figure1
50
Plasma corticosterone responses to the intrapituitary injection of saline (Sal) or CRF 30 set after injection of indomethacin (Ind) or buffer vehicle (Buff).
p<:
40 30 20 10 0 : Buff
JULY 1977 VOL. 14 NO. 1
Ind
147
PROSTAGLANDINS
Although Ind is known to inhibit PG synthesis, it certainly could have a variety of other effects, and any one of these might conceivably be responsible for the findings presented in Fig. 1. In an attempt to control for this, we performed the experiments whose results are given in Fig. 2. In these cases, various exogenous PCs were mixed with the CRF preparation (or saline) and injected 30 set after the injection of the Ind. In anterior pituitaries stimulated by Ind and CRF, the PGs tested decreased the magnitude of this response to varying degrees. In the absence of CRF the stimulator-yeffect of the Ind was not reduced to a significant extent by any of the PGs, but the pattern of these data is virtually identical to that seen in the presence of CRF.
Ind, then PG plus SaIDor
CRF m
,c
P
3”
70
2
60
z if i9
50 40
g
30
8
20
g
lo 0
6
2
PG:
Veh
AI
El
Fl
Bl
Figure 2 Plasma corticosterone responses to sequential intrapituitary injections as described in Fig. 1, except all rats received indomethacin, and the saline or CRF was added to the indicated PGs or their vehicle (Veh).
DISCUSSION The present results demonstrate that the PG synthesis inhibitor, Ind, causes a rapid increase in ACTH secretion in the presence, and in the absence, of stimulation by CRF. In the former case, this effect was reversed by exogenous PGs, but in the latter case, such reversal was not statistically significant. This might imply that the PGs block only CRF, but not Ind, stimulated ACTH secretion. However, the fact that the patterns of the responses were virtually identical in the two cases argues against this suggestion. Although of opposite polarity, these results are reminiscent of the finding that several PGs, while
148
JULY 1977 VOL. 14 NO. 1
PROSTAGLANDINS
failing to alter TSH secretion on their own, will increase the sensitivity of the pituitary to stimulation by TRH (11). The fact that the reversal of the Ind-CSF stimulation by exogenous PGs is only a partial reversal is consistent with earlier studies in which the PGs only partially inhibited the response to CRF alone (5). It is possible that a larger amount of any given PC might completely reverse such effects. However, it is equally plausible that a particular blend of various PGs is necessary for the maintenance of normal pituitary responsiveness to CRF. Finally, it should be noted that Ind can block phosphodiesterase activity, and that cyclic AMP can act at the pituitary to stimulate ACTH secretion (12). Thus, the fact that the suppressive effect of the PGs is only partial could be a result of increased pituitary cyclic AMP levels which would oppose the effect of the PGs. Of the PGs tested in the present work, PGBl was found to be the most potent inhibitor (i.e., in reversing the stimulation by In&CRF). It has previously been found that this particular PG is also the most active inhibitor of the responsiveness to CPF alone (5). It is interesting to note that PGs of the B series are not particularly potent in cases in which the effect is stimulatory rather than inhibitory to pituitary secretion, such as TSH (11, 13) or GH (13). Also, PGBl has a relatively low potency regarding its hypothalamic stimulatory effect on the secretion of-CRF-ACM (4, 5) or of LRH-LH (14). Thus, among the variety of PGs tested for effects on several different anterior pituitary hormones, the PGs of the B series appear to have relatively high potency in inhibitory processes, but relatively low potency in stimulatory processes. It should be noted that the present studies have made use of an indirect index of ACTH secretion, namely plasma corticosterone levels. In such csaes, it is imperative that it be known that the substances injected stereotaxically are not spreading to , and acting at, the adrenal gland itself. In previous studies (4, 51, we have demonstrated that the intravenous administration of these amounts of the PGs, and up to five times this amount of the CSF preparation, are completely inactive. Similarly, in the present work we have ruled out such a possibility for Ind by administering it intravenously and finding it to be completely ineffective. Thus, all three substances can be assumed to be acting directly at the anterior pituitary. Although others have shown that systemically administered Ind significantly decreases PG concentrations in the pituitary (151, we have not made such measurements in the present study. Even if such measurements were made, it would not be particularly surprising to find that the PG content of the whole pituitary might not be decreased by the Ind. The reason for this is that our injections perfuse only a portion of the pituitary. However, the fact that such effects are at least partially reversed by exogenous PGs suggests that the action of the drug is due to its inhibition of PG synthesis, rather than to some non-specific side effect of the drug. Finally, it is interesting to note that the present results, taken with previous results regarding the effects of Ind and PGs on TSH secretion, are quite consistent with the suggested inverse relationship between the secretions of TSH and ACTH (16). It is already known (17) that Ind will inhibit TSH secretion induced either by TRH or by thyroidectomy, and the present results indicate that Ind has just the opposite effect on ACTH secretion. It is not certain that this inverse coupling occurs at the level of the pituitary (18). However, if it does, then the PGe might well play some role in mediating this phenomenon.
JULY 1977 VOL. 14 NO. 1
149
PROSTAGLANDINS
1.
Hedge, G.A. Roles for the prostaglandins in the regulation of anterior pituitary secretion. Life Sciences '0: 17, 1977.
2.
de Wied, D., A. Witter, D.H.G. Versteeg, and A.H. Mulder. of ACTH by substances of central nervous system origin. Endocrinology @: 561, 1969.
3.
Peng, T.-C., K.M. Six, and P.L. Munson. Effects of prostaglandin El on the hypothalamo-hypophyseal-adrenocortical axis in rats. Endocrinology 86: 202, 1970.
Release
4. Hedge, G.A. and S.D. Hanson. secretion.
The effects of prostaglandins on ACTH Endocrinology 91: 925, 1972.
5. Hedge, G.A. Hypothalamic and pituitary effects of prostaglandins on ACTH secretion. Prostaglandins 2: 293, 1976. 6. Hedge, G.A., M.B. Yates, R. Marcus, and F.E. Yates. of vasopressin in causing corticotropin release. 328-340, 1966.
Site of action Endocrinology 2:
7. Brown, M.R. and G.A. Hedge.
TSH and ACTH secretion after intrapituitary injection of synthesis TRF. Endocrinology 91: 206, 1972.
a. Armstrong, D.T. and D.L. Grinwich. Blockade of spontaneous and LHinduced ovulation in rats by indomethacin, an inhibitor of prostaglandin synthesis. Prostaglandins 1: 21, 1972.
9. Glick, D., D. van Redlich, and S. Levine.
Fluorometric determination of corticosterone and cortisol in 0.02-0.05 milliliters of plasma or submilligram samples of adrenal tissue. Endocrinology fi: 653, 1964.
10.
Brown, M.R. and G.A. Hedge. Thyroid secretion in the unanesthetized, stress-free rat and its suppression by pentobarbital. Neuroendocrinology 9: 158, 1972.
11.
In viva effects of prostaglandins on Brown, M.R. and G.A. Hedge. -TRH-induced TSH secretion. Endocrinology 95: 1392, 1974.
12.
Hedge, G.A. ACTH secretion due to hypothalamo-pituitary effects of adenosine - 3', 5' - monophosphate and related substances. Endocrinology &_: 500, 1971. Drouin, J. and F. Labrie. Specificity of the stimulatory effect of prostaglandins on hormone release in rat anterior pituitary cells in culture. Prostaglandins &l_: 355, 1976.
13.
14. Warberg, J., R.L. Eskay, and J.C. Porter.
Prostaglandin-induced release of anterior pituitary hormones: Structure-activity relationships. Endocrinology 98: 1135, 1976. Ovulation blockade by aspirin or indomethacin - -in viva evidence for a role of prostaglandin in gonadotropin secretion. Prostaglandins 1: 3, 1972.
15. Orczyk, G.P. and H.R. Behrman.
Hypothalamic control of concomitant secretion of ACTH Mem. Sot. Endocrin. 17: 19, 1968.
16. Guillemin, R. and TSH.
Suppression of TSH secretion by prostaglandin synthesis inhibitors. Endocrinology 98: 787, 1976.
l-c. Thompson, M.E. and G.A. Hedge.
18. Fortier, C., A. Delgado, P. Ducommun, S. Ducommun, A. DuPont, M. Jobin, J. Krailer, B. Macintosh-Hardt, H. Marceau, P. Mialhe, C. Mialhe-Voloss, C. Rex-up, and G.P. van Rees. Functional interrelationships between the adenohypophysis, thyroid, adrenal cortex, and gonads. can. Med. Assoc. J. -103: 864, 1970. Received
150
2/4/77
- Approved
6/l/77
JULY 1977 VOL. 14 NO. 1
STIMULATION OF ACTH SECRETION BY INDOMETHACIN AND REVERSAL BY EXOGENOUS PROSTAGLANDINSl
G.A. Hedge2
Department of Physiology Arizona Health Science Center University of Arizona Tucson, Arizona
85724
ABSTRACT
The prostaglandin (PG) synthesis inhibitor, indomethacin, has been found to enhance adrenocorticotropin (ACTH) secretion upon injection directly into the anterior pituitary at a dose that is ineffective intravenously. Such stimulation was observed in combination with, and in the absence of, stimulation by a corticotropin-releasingfactor (CRF) preparation. It was reversed to varying degrees by replacing certain PGs exogenously. It is suggested that endogenous PGs in the anterior pituitary participate in the modulation of the sensitivity of this gland to the hypothalamic neurohormone, CRF.
ACKNOWLEDGEMENT
The technical assistance of Ms. Dona Clark and Ms. Nancy Hernden is gratefully acknowledged.
1These studies were supported by USPHS Research Grant AM 13794. 2 Present address: Department of Physiology, West Virginia Medical Center, Morgantown, West Virginia
JULY 1977 VOL. 14 NO. 1
26506
145
PROSTAGLANDINS
INTRODUCTION
It is now recognized that the prostaglandins (PG) can affect the function of the hypothalamo-pituitary-adrenalaxis at multiple sites (1). The most striking, and the most well documented, of these effects is the stimulatory effect of exogenous PGs exerted at the level of the hypothalamus (2, 3, 4). Although studies such as these suggested that the PGs had no effect at the level of the anterior pituitary, subsequent work has shown that'the PGs can indeed alter ACTR secretion by acting at this level (5). In contrast to the hypothalamic effect, this pituitary effect is inhibitory in nature and it is of relatively low magnitude. Although it seems quite clear that the PGs can suppress pituitary responsiveness to a CRF preparation, it is not known whether this effect is of physiological importance. The possibility that this is simply a pharmacological effect, completely unrelated to endogenous PGs, must certainly be considered. The present experiments attempt to make this distinction by studying both basal and CRF-stimulatedACTH secretion after blocking the synthesis of endogenous PGs with the drug indomethacin (Id). In addition, we have attempted to reverse the effects of Ind by providing PGs exogenously.
MATERIALS
ANDMETHODS
Female Sprague-Dawley rats from our own breeding colony (started from Charles River CD rats) weighing 180-230 grams were used throughout these experiments. The animals were fed Purina Rat Chow and given tap water ad libitum. They were housed in temperature and humidity controlled quzxh a cycle of 12 hours of light and 12 hours of dark. In order to circumvent the extra-pituitary effects of the PGs or Ind, these substances were injected stereotaxically directly into the anterior pituitary in all of these experiments. This was accomplished under pentobarbital anesthesia (4.5 mg/lOO g body weight) by a technique that has been described in detail elsewhere (6, 7). In brief, a small (200-300 u o.d.) glass cannula was stereotaxicallyplaced into the anterior pituitary from the dorsal aspect. The rate of injection was always 2 ~1 per min., and each injection was followed with a similar injection of toluidine blue dye to assist in the assessment of the extent of the distribution of the test material. Injection volumes and doses were as follows: CRF, 0.02 median eminence equivalents in 1 ~1; Ind, 50 ug in 5 ~1; PG, 2 pg in 2 ~1. All rats were pre-treated with dexamethasone (25 ug/lOO g body wt., subcutaneously) 3-6 hours prior to injection in order to prevent the ACTH secretion that would normally be evoked by the stereotsxic procedure. In the one case in which Ind was injected intravenously as a control, the substance was diluted to 0.5 ml with physiological saline and then injected into a lateral tail vein. The PGs used in these experiments were a gift from Dr. John E. Pike, Upjohn Company, Kalamazoo, Michigan. They were prepared by dissolving them in 95% ethanol and then adding nine parts 0.02% NaC03 to one part
JULY 1977 VOL. 14 NO. 1
PROSTAGLANDINS
of the ethanol. Aliquots of the stock solutions adequate for one day's work were capped under nitrogen and stored refrigerated. The hypothalamic extract used ss a CRF was kindly provided by the NIAMDD Hormone Distribution Program. This lyophilized preparation was reconstituted with water, aliquoted, and stored frozen (-2OC) until use, at which time, it was diluted with saline so that 1 ul contained 0.02 median eminence equivalents. Ind was dissolved in 0.1 M NaPOh buffer as described by Armstrong and Grinwich (8). All substances to be microinjected had pH values that lay between 6.0 and 7.8. Fifteen minutes after the beginning of the injection of the Ind (or buffer control), the rats were decapitated and trunk blood was collected. Plasma was stored frozen until fluorometric assay for corticosterone as et al an index of ACTH secretion. The method used was that of Glick --3 (9) with minor modification (10). All data are presented as means accompanied by their standard errors. The number of rats comprising each group is indicated on the histogram bars. Student's t-test (Fig. 1) and Dunnett's multiple comparison test (Fig. 2) were used to establish the significance of differences between groups.
RESULTS The data in Fig. 1 demonstrate the effect of Ind on ACTH secretion from unstimulated pituitaries, and from those stimulated by the CRF preparation. The dose of CRF was chosen from our previous experience (5) as one that will elicit a rather small response. In the present work, it can be seen that this dose elicits a significant (pXO.02) increase in ACTH secretion (see buffer control data on the left side of Fig. 1). Whether the pituitaries have been stimulated or not, the Ind elicits a striking increase in ACTH secretion. This cannot be due to the spread of the Ind to the adrenal since this same dose of the drug given intravenously fails to elicit any ACTH secretion (4.3 * 1.1 ug/dl).
Figure1
50
Plasma corticosterone responses to the intrapituitary injection of saline (Sal) or CRF 30 set after injection of indomethacin (Ind) or buffer vehicle (Buff).
p<:
40 30 20 10 0 : Buff
JULY 1977 VOL. 14 NO. 1
Ind
147
PROSTAGLANDINS
Although Ind is known to inhibit PG synthesis, it certainly could have a variety of other effects, and any one of these might conceivably be responsible for the findings presented in Fig. 1. In an attempt to control for this, we performed the experiments whose results are given in Fig. 2. In these cases, various exogenous PCs were mixed with the CRF preparation (or saline) and injected 30 set after the injection of the Ind. In anterior pituitaries stimulated by Ind and CRF, the PGs tested decreased the magnitude of this response to varying degrees. In the absence of CRF the stimulator-yeffect of the Ind was not reduced to a significant extent by any of the PGs, but the pattern of these data is virtually identical to that seen in the presence of CRF.
Ind, then PG plus SaIDor
CRF m
,c
P
3”
70
2
60
z if i9
50 40
g
30
8
20
g
lo 0
6
2
PG:
Veh
AI
El
Fl
Bl
Figure 2 Plasma corticosterone responses to sequential intrapituitary injections as described in Fig. 1, except all rats received indomethacin, and the saline or CRF was added to the indicated PGs or their vehicle (Veh).
DISCUSSION The present results demonstrate that the PG synthesis inhibitor, Ind, causes a rapid increase in ACTH secretion in the presence, and in the absence, of stimulation by CRF. In the former case, this effect was reversed by exogenous PGs, but in the latter case, such reversal was not statistically significant. This might imply that the PGs block only CRF, but not Ind, stimulated ACTH secretion. However, the fact that the patterns of the responses were virtually identical in the two cases argues against this suggestion. Although of opposite polarity, these results are reminiscent of the finding that several PGs, while
148
JULY 1977 VOL. 14 NO. 1
PROSTAGLANDINS
failing to alter TSH secretion on their own, will increase the sensitivity of the pituitary to stimulation by TRH (11). The fact that the reversal of the Ind-CSF stimulation by exogenous PGs is only a partial reversal is consistent with earlier studies in which the PGs only partially inhibited the response to CRF alone (5). It is possible that a larger amount of any given PC might completely reverse such effects. However, it is equally plausible that a particular blend of various PGs is necessary for the maintenance of normal pituitary responsiveness to CRF. Finally, it should be noted that Ind can block phosphodiesterase activity, and that cyclic AMP can act at the pituitary to stimulate ACTH secretion (12). Thus, the fact that the suppressive effect of the PGs is only partial could be a result of increased pituitary cyclic AMP levels which would oppose the effect of the PGs. Of the PGs tested in the present work, PGBl was found to be the most potent inhibitor (i.e., in reversing the stimulation by In&CRF). It has previously been found that this particular PG is also the most active inhibitor of the responsiveness to CPF alone (5). It is interesting to note that PGs of the B series are not particularly potent in cases in which the effect is stimulatory rather than inhibitory to pituitary secretion, such as TSH (11, 13) or GH (13). Also, PGBl has a relatively low potency regarding its hypothalamic stimulatory effect on the secretion of-CRF-ACM (4, 5) or of LRH-LH (14). Thus, among the variety of PGs tested for effects on several different anterior pituitary hormones, the PGs of the B series appear to have relatively high potency in inhibitory processes, but relatively low potency in stimulatory processes. It should be noted that the present studies have made use of an indirect index of ACTH secretion, namely plasma corticosterone levels. In such csaes, it is imperative that it be known that the substances injected stereotaxically are not spreading to , and acting at, the adrenal gland itself. In previous studies (4, 51, we have demonstrated that the intravenous administration of these amounts of the PGs, and up to five times this amount of the CSF preparation, are completely inactive. Similarly, in the present work we have ruled out such a possibility for Ind by administering it intravenously and finding it to be completely ineffective. Thus, all three substances can be assumed to be acting directly at the anterior pituitary. Although others have shown that systemically administered Ind significantly decreases PG concentrations in the pituitary (151, we have not made such measurements in the present study. Even if such measurements were made, it would not be particularly surprising to find that the PG content of the whole pituitary might not be decreased by the Ind. The reason for this is that our injections perfuse only a portion of the pituitary. However, the fact that such effects are at least partially reversed by exogenous PGs suggests that the action of the drug is due to its inhibition of PG synthesis, rather than to some non-specific side effect of the drug. Finally, it is interesting to note that the present results, taken with previous results regarding the effects of Ind and PGs on TSH secretion, are quite consistent with the suggested inverse relationship between the secretions of TSH and ACTH (16). It is already known (17) that Ind will inhibit TSH secretion induced either by TRH or by thyroidectomy, and the present results indicate that Ind has just the opposite effect on ACTH secretion. It is not certain that this inverse coupling occurs at the level of the pituitary (18). However, if it does, then the PGe might well play some role in mediating this phenomenon.
JULY 1977 VOL. 14 NO. 1
149
PROSTAGLANDINS
1.
Hedge, G.A. Roles for the prostaglandins in the regulation of anterior pituitary secretion. Life Sciences '0: 17, 1977.
2.
de Wied, D., A. Witter, D.H.G. Versteeg, and A.H. Mulder. of ACTH by substances of central nervous system origin. Endocrinology @: 561, 1969.
3.
Peng, T.-C., K.M. Six, and P.L. Munson. Effects of prostaglandin El on the hypothalamo-hypophyseal-adrenocortical axis in rats. Endocrinology 86: 202, 1970.
Release
4. Hedge, G.A. and S.D. Hanson. secretion.
The effects of prostaglandins on ACTH Endocrinology 91: 925, 1972.
5. Hedge, G.A. Hypothalamic and pituitary effects of prostaglandins on ACTH secretion. Prostaglandins 2: 293, 1976. 6. Hedge, G.A., M.B. Yates, R. Marcus, and F.E. Yates. of vasopressin in causing corticotropin release. 328-340, 1966.
Site of action Endocrinology 2:
7. Brown, M.R. and G.A. Hedge.
TSH and ACTH secretion after intrapituitary injection of synthesis TRF. Endocrinology 91: 206, 1972.
a. Armstrong, D.T. and D.L. Grinwich. Blockade of spontaneous and LHinduced ovulation in rats by indomethacin, an inhibitor of prostaglandin synthesis. Prostaglandins 1: 21, 1972.
9. Glick, D., D. van Redlich, and S. Levine.
Fluorometric determination of corticosterone and cortisol in 0.02-0.05 milliliters of plasma or submilligram samples of adrenal tissue. Endocrinology fi: 653, 1964.
10.
Brown, M.R. and G.A. Hedge. Thyroid secretion in the unanesthetized, stress-free rat and its suppression by pentobarbital. Neuroendocrinology 9: 158, 1972.
11.
In viva effects of prostaglandins on Brown, M.R. and G.A. Hedge. -TRH-induced TSH secretion. Endocrinology 95: 1392, 1974.
12.
Hedge, G.A. ACTH secretion due to hypothalamo-pituitary effects of adenosine - 3', 5' - monophosphate and related substances. Endocrinology &_: 500, 1971. Drouin, J. and F. Labrie. Specificity of the stimulatory effect of prostaglandins on hormone release in rat anterior pituitary cells in culture. Prostaglandins &l_: 355, 1976.
13.
14. Warberg, J., R.L. Eskay, and J.C. Porter.
Prostaglandin-induced release of anterior pituitary hormones: Structure-activity relationships. Endocrinology 98: 1135, 1976. Ovulation blockade by aspirin or indomethacin - -in viva evidence for a role of prostaglandin in gonadotropin secretion. Prostaglandins 1: 3, 1972.
15. Orczyk, G.P. and H.R. Behrman.
Hypothalamic control of concomitant secretion of ACTH Mem. Sot. Endocrin. 17: 19, 1968.
16. Guillemin, R. and TSH.
Suppression of TSH secretion by prostaglandin synthesis inhibitors. Endocrinology 98: 787, 1976.
l-c. Thompson, M.E. and G.A. Hedge.
18. Fortier, C., A. Delgado, P. Ducommun, S. Ducommun, A. DuPont, M. Jobin, J. Krailer, B. Macintosh-Hardt, H. Marceau, P. Mialhe, C. Mialhe-Voloss, C. Rex-up, and G.P. van Rees. Functional interrelationships between the adenohypophysis, thyroid, adrenal cortex, and gonads. can. Med. Assoc. J. -103: 864, 1970. Received
150
2/4/77
- Approved
6/l/77
JULY 1977 VOL. 14 NO. 1