1166
27. 28. 29. 30.
31. 32.
COMMENTS
Wiswell, Endocrinology, Supplement, 96: A153, 1975. Fisher, D. A., and T. H. OddieJ Clin Endocrinol Metab 28: 1690, 1968. Braverman, L. E., and S. H. Ingbar, J Clin Endocrinol Metab 27: 389, 1967. Federman, D. D., J. Robbins, and J. E. Rail, J Clin Invest 37: 1024, 1958. Paulsen, C. A., D. L. Gordon, R. W. Carpenter, H. M. Gandy, and W. D. Drucker, Recent Prog Honn Res 24: 321, 1968. Fukutan.i, K., K. Isurugi, H. Takayasu, K. VVakabayashi, and B. Tamaoki, J Clin Endocrinol Metab'39: 856, 1974. Lee, P. A., R. B. Jaffe, A. R. Midgley, Jr., F. Kohen, and G. D. Niswender J Clin Endocrinol Metab 35: 636, 1972.
JCK & M • 1975 Vol 41 • No 6
33. Capell, P. T., C. A. Paulsen, D. Derleth, R. Skoglund, and S. Plymate J Clin Endocrinol Metab 37: 752, 1973. 34. Hagen, C., A. S. McNeilly, M. Arroe, K. Emmertsen, and A. Froland, Lancet 2: 57, 1974. 35. Arroyo, L. A. H., P. Detolle, and M. L'Hermite, Nouv Presse Med 2 (43): 2898, 1973. 36. Yen, S. S. C., Y. Ehara, and T. M. SilerJ Clin Invest 53: 652, 1974. 37. Longcope, C., D. S. Layne, and J. F. Tait, J Clin Invest 47: 93, 1968. 38. MacDonald, P. C., R. P. Rombaut, and P. K. Siiteri, J Clin Endocrinol Metab 27: 1103, 1967. 39. Ahmad, N., and W. I. Morse, CanadJ Biochem 43: 25, 1965. 40. Longcope, C., T. Kato, and R. Horton,/ Clin Invest 48: 2191, 1969.
The Effect of Chlorpromazine on Plasma Renin Activity and Aldosterone in Man DAVID ROBERTSON * AND ANDREW M. MICHELAKIS Clinical Pharmacology Program, Departments of Pharmacology and Medicine, Michigan State University, East Lansing, Michigan and Vanderbilt University, Nashville, Tennessee ABSTRACT. The response of plasma renin activity (PRA) and aldosterone to the intravenous administration of chlorpromazine was determined in schizophrenic patients while they were supine and on a normal sodium diet. In all subjects PRA and aldosterone increased during chlorpromazine administration with little or no change in blood pressure. The
maximum PRA and aldosterone levels occurred 60 min after the higher dose of chlorpromazine. These data suggest that chlorpromazine affects the reninangiotensin-aldosterone system and it may interfere with the evaluation of this system in patients receiving this drug. (J Clin Endocrinol Metab 41: 1166, 1975)
T is now well established that the sympathetic nervous system plays an important role in mediating renin secretion. Both in vitro (1) and in vivo (2-4) studies have demonstrated that catecholamines will increase renin release, and stimulation of the renal nerves produces an enhanced renin output (2) from the kidney. Insulin-induced hypoglycemia also stimulated plasma renin activity (PRA), this effect being lessened by adrenal denervation but unaffected by renal denervation (5). The effect of hypoglycemia on PRA has been shown to be potentiated by the alpha-blocker phenoxybenzamine and abolished by the beta-blocker propranolol (6).
Stimulation of the pressor region of the medulla oblongata has also been shown to stimulate PRA (7) with increasing blood pressure and decreasing glomerular filtration rate (8). Although this was blocked by renal denervation, it was unaffected by phenoxybenzamine, which blocks sympathetic effects on the renal vasculature (9). Propranolol, which has been shown to decrease PRA in man (10), reduced or abolished this response (11). Studies such as the above indicate that many pharmacologic agents act on the reninaldosterone hormonal system both directly at the level of the kidney and indirectly by the autonomic nervous system and that the effect of the sympathetic nervous system on renin release may be mediated through beta receptors. Chlorpromazine and the phenothiazine derivatives are among the most widely used drugs in medical practice. Chlorpromazine has been shown to affect blood pressure (12) and its
I
Received February 18, 1975. Supported in part by U.S. Public Health Service Giants HL 18019 and HL 18027. *Presently at the Johns Hopkins Hospital, Baltimore, Maryland.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 21:21 For personal use only. No other uses without permission. . All rights reserved.
1167
COMMENTS alpha-adrenergic blocking properties have been studied in several species (13,14). There are now suggestions that chlorpromazine may have some beta adrenergic activity (15). Because of these properties of chlorpromazine it is possible that it may affect the renin-aldosterone hormonal system and some of its clinical effects may be explained by this mechanism. A study, therefore, has been performed to determine its effect on plasma renin and aldosterone in man and the results are reported here.
1200
900 RENIN ACTIVITY ng/100 ml
300
The effect of acute administration of chlorpromazine on PRA, plasma aldosterone, and blood pressure was studied in 12 patients in the Neuropsychiatric ward. The nature of the study was fully explained to the patients and informed consent was obtained. All subjects were Caucasian and under the age of 40. Although some of them had been treated with phenothiazine antipsychotics in the past, none had received treatment for at least one week prior to the study. All subjects were on a diet consisting of 150 mEq of sodium. None of them was hypertensive or had any evidence of cardiovascular or renal disease. Because of the diurnal variation in PRA and aldosterone (3) all studies were conducted in the morning starting at 8 AM. On the day of the study, the subjects
900 RENIN ACTIVITY ng/100 ml 600
300
30
rfi Baseline
3°
60
120
20 ALDOSTERONE ng/100 ml 10
30
60
120
180
Baseline TIME IN MINUTES FOLLOWING 10 mg CHLORPROMAZINE ADMINISTRATION
FIG. 2. The effect of 10 mg of chlorpromazine upon plasma renin activity and aldosterone levels. All subjects were supine during the study. Results show mean ± SEM. remained supine from midnight until the completion of the study. They received breakfast at 6 AM. At 8 AM butterfly IV was placed on the right arm for infusion and blood sampling. At 8:30 AM and 8:45 AM, control blood samples were taken. At 9 AM the subjects were given either 25 or 10 mg of chlorpromazine slowly intravenously. Blood samples for PRA and aldosterone were then taken at 9:30, 10:00, 11:00 AM and 12:00 noon. These samples were thus taken 30,60,120, and 180 min after the administration of chlorpromazine. In all subjects, blood pressure was determined at specified intervals during the study. The PRA was measured by the radioimmunoassay method (16) and is reported in nanograms (ng) of angiotensin/100 ml of plasma generated during a 3h incubation period. Plasma aldosterone was measured by a method described elsewhere (17) and is expressed in ng/100 ml of plasma.
1200-
20
rfl
30-
Materials and Methods
ALDOSTERONE ng/100 ml
rti
Results 180
TIME IN MINUTES FOLLOWING 25 mg CHLORPROMAZINE ADMINISTRATION
FIG. 1. The effect of 25 mg of chlorpromazine upon plasma renin activity and aldosterone levels. All subjects were supine during the study. Results show mean ± SEM.
Effect of intravenous administration of 25 rag of chlorpromazine on PRA and aldosterone. Twenty-five mg of chlorpromazine was given to 5 patients. All subjects responded with a rise in PRA and aldosterone. The maximum rise in PRA from the control levels of 343 ± 60 (SEM) ng/100 ml to 1018 ± 160 (SEM) ng/100 ml occurred 60 min after chlorpromazine administration (Fig. 1).
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 21:21 For personal use only. No other uses without permission. . All rights reserved.
1168
COMMENTS
Subsequently the PRA declined until at 180 min it was 645 ± 120. Applying Student's t test to paired individual changes from control to the 60 minute sample revealed these changes to be significant at the 0.05 level. An average blood pressure decrease of 10/2 mm Hg was observed but was not statistically significant. In individual patients the changes in PRA did not bear close relationship to concomitant blood pressure recordings. Since patients remained supine throughout the study postural hypotension could not be observed. The plasma aldosterone levels tended to parallel the PRA levels with the maximum also at 60 min (Fig. 1). The rise in plasma aldosterone observed at 60 min was significant at the 0.05 level. Effect of intravenous administration of 10 mg of chlorpromazine on PRA and aldosterone. Ten mg of chlorpromazine was given to 7 patients. There were no changes in systemic blood pressure during the study. PRA rose in all patients studied (Fig. 2) but with the small sample size, levels of significance were not reached. However, the plasma aldosterone levels at 60 and 120 min after chlorpromazine were significantly elevated, as they had been with the 25 mg dose (Fig. 2). No changes in serum concentration of electrolytes were noted during these studies with either the 10 mg or 25 mg dosage. Discussion Renin secretion is affected by various endogenous and exogenous stimuli (18) and many drugs are known to act on the renin-angiotensinaldosterone system (1,3,6,10) both directly and indirectly. Now that the level of PRA may have therapeutic significance, it is important that the effects of commonly used drugs on renin and aldosterone be known in order to avoid misinterpretation of data used in the diagnosis of renal or adrenal abnormalities. The results of the present study indicate that chlorpromazine affects the renin-aldosterone system. The intravenous administration of chlorpromazine dramatically elevated plasma aldosterone levels and PRA, and the response of the aldosterone was as great with the 10 mg dose as with the 25 mg dose. All these changes occurred without significant change in systemic blood pressure or pulse. Since PRA is known to be increased by beta agonists, these findings are consistent with the hypothesis that chlorpromazine possesses some
JCE & M • 1975 Vol 41 • No 6
beta adrenergic activity. However, there are other possibilities that cannot be excluded. There could be PRA stimultion by a centrally mediated drug effect on the autonomic nervous system directly or via the adrenal medulla. Although the systemic blood pressure did not change, it is possible that there were local changes at the level of the renal baroreceptor or alterations in renal blood flow. Although no definite explanation for the elevated PRA and plasma aldosterone after chlorpromazine administration is offered, the magnitude of the change deserves consideration. With the increasing use of PRA and aldosterone to screen patients for possible renal and adrenal pathology, data on patients receiving phenothiazines may be misinterpreted as implying underlying pathology. Of great interest is the impressive stimulation of aldosterone found after the lower dose of chlorpromazine. The effects of chronic oral administration of chlorpromazine on the kidney and the adrenal cortex merit further investigation. References 1. Michelakis, A. M., J. Caudle, and G. W. Liddle,Proc Soc Exp Biol Med 130: 748, 1969. 2. Vander, A. J., Am J Physiol 209: 659, 1955. 3. Michelakis, A. M., and R. Horton, Circ Res (suppl) 27: 185, 1970. 4. Menzie, J., A. M. Michelakis, and H. Yoshida, AmJ Physiol 227: 1281, 1974. 5. Otsuka, K., T. Assaykeen, A. Goldfien, and W. F. Ganong, Endocrinology 187: 1306, 1970. 6. Assaykeen, T., P. L. Clayton, A. Goldfien, and W. F. Ganong, Endocrinology 187: 1318, 1970. 7. Passo, S. S., T. Assaykeen, K. Otsuka, B. L. Wise, A. Goldfien, and W. F. Ganong, Neuroendocrinology 7: 1, 1971. 8. Wise, B. L., and W. F. Ganong, Am J Physiol 198: 1291, 1960. 9. Gump, F. E., T. Magill, A. P. Thai, and J. M. Kinney, Surg Gynecol Obstet 127: 319, 1968. 10. Michelakis, A. M., and R. G. McAllister, J Clin Endocrinol Metab 34: 386, 1972. 11. Passo, S. S., T. Assaykeen, A. Goldfien, and W. F. Ganong, Neuroendocrinology 7: 97, 1971. 12. Moyer, J. H.J Clin Exp Psychopathol 16:179,1955. 13. Martin, W. R., J. L. Riehl, and K. R. UnnaJ Pharm Exp Ther 130: 37, 1960. 14. Gokhale, S. D., O. D. Gulati, and H. M. Parikh, BrJ Pharmacol 23: 508, 1964. 15. Webster, R. A., BrJ Pharmacol 25: 566, 1965. 16. Haber, E., T. Koerner, L. B. Page, B. Kliman, and A. PumodeJ Clin Endocrinol Metab 29: 1349, 1969. 17. Mayes, D., S. Furuyama, D. C. Kern, and C. A. Nugent, 7 Clin Endocrinol Metab 30: 682, 1970. 18. Vander, A. J., Physiol Rev 47: 359, 1967.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 21:21 For personal use only. No other uses without permission. . All rights reserved.
27. 28. 29. 30.
31. 32.
COMMENTS
Wiswell, Endocrinology, Supplement, 96: A153, 1975. Fisher, D. A., and T. H. OddieJ Clin Endocrinol Metab 28: 1690, 1968. Braverman, L. E., and S. H. Ingbar, J Clin Endocrinol Metab 27: 389, 1967. Federman, D. D., J. Robbins, and J. E. Rail, J Clin Invest 37: 1024, 1958. Paulsen, C. A., D. L. Gordon, R. W. Carpenter, H. M. Gandy, and W. D. Drucker, Recent Prog Honn Res 24: 321, 1968. Fukutan.i, K., K. Isurugi, H. Takayasu, K. VVakabayashi, and B. Tamaoki, J Clin Endocrinol Metab'39: 856, 1974. Lee, P. A., R. B. Jaffe, A. R. Midgley, Jr., F. Kohen, and G. D. Niswender J Clin Endocrinol Metab 35: 636, 1972.
JCK & M • 1975 Vol 41 • No 6
33. Capell, P. T., C. A. Paulsen, D. Derleth, R. Skoglund, and S. Plymate J Clin Endocrinol Metab 37: 752, 1973. 34. Hagen, C., A. S. McNeilly, M. Arroe, K. Emmertsen, and A. Froland, Lancet 2: 57, 1974. 35. Arroyo, L. A. H., P. Detolle, and M. L'Hermite, Nouv Presse Med 2 (43): 2898, 1973. 36. Yen, S. S. C., Y. Ehara, and T. M. SilerJ Clin Invest 53: 652, 1974. 37. Longcope, C., D. S. Layne, and J. F. Tait, J Clin Invest 47: 93, 1968. 38. MacDonald, P. C., R. P. Rombaut, and P. K. Siiteri, J Clin Endocrinol Metab 27: 1103, 1967. 39. Ahmad, N., and W. I. Morse, CanadJ Biochem 43: 25, 1965. 40. Longcope, C., T. Kato, and R. Horton,/ Clin Invest 48: 2191, 1969.
The Effect of Chlorpromazine on Plasma Renin Activity and Aldosterone in Man DAVID ROBERTSON * AND ANDREW M. MICHELAKIS Clinical Pharmacology Program, Departments of Pharmacology and Medicine, Michigan State University, East Lansing, Michigan and Vanderbilt University, Nashville, Tennessee ABSTRACT. The response of plasma renin activity (PRA) and aldosterone to the intravenous administration of chlorpromazine was determined in schizophrenic patients while they were supine and on a normal sodium diet. In all subjects PRA and aldosterone increased during chlorpromazine administration with little or no change in blood pressure. The
maximum PRA and aldosterone levels occurred 60 min after the higher dose of chlorpromazine. These data suggest that chlorpromazine affects the reninangiotensin-aldosterone system and it may interfere with the evaluation of this system in patients receiving this drug. (J Clin Endocrinol Metab 41: 1166, 1975)
T is now well established that the sympathetic nervous system plays an important role in mediating renin secretion. Both in vitro (1) and in vivo (2-4) studies have demonstrated that catecholamines will increase renin release, and stimulation of the renal nerves produces an enhanced renin output (2) from the kidney. Insulin-induced hypoglycemia also stimulated plasma renin activity (PRA), this effect being lessened by adrenal denervation but unaffected by renal denervation (5). The effect of hypoglycemia on PRA has been shown to be potentiated by the alpha-blocker phenoxybenzamine and abolished by the beta-blocker propranolol (6).
Stimulation of the pressor region of the medulla oblongata has also been shown to stimulate PRA (7) with increasing blood pressure and decreasing glomerular filtration rate (8). Although this was blocked by renal denervation, it was unaffected by phenoxybenzamine, which blocks sympathetic effects on the renal vasculature (9). Propranolol, which has been shown to decrease PRA in man (10), reduced or abolished this response (11). Studies such as the above indicate that many pharmacologic agents act on the reninaldosterone hormonal system both directly at the level of the kidney and indirectly by the autonomic nervous system and that the effect of the sympathetic nervous system on renin release may be mediated through beta receptors. Chlorpromazine and the phenothiazine derivatives are among the most widely used drugs in medical practice. Chlorpromazine has been shown to affect blood pressure (12) and its
I
Received February 18, 1975. Supported in part by U.S. Public Health Service Giants HL 18019 and HL 18027. *Presently at the Johns Hopkins Hospital, Baltimore, Maryland.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 21:21 For personal use only. No other uses without permission. . All rights reserved.
1167
COMMENTS alpha-adrenergic blocking properties have been studied in several species (13,14). There are now suggestions that chlorpromazine may have some beta adrenergic activity (15). Because of these properties of chlorpromazine it is possible that it may affect the renin-aldosterone hormonal system and some of its clinical effects may be explained by this mechanism. A study, therefore, has been performed to determine its effect on plasma renin and aldosterone in man and the results are reported here.
1200
900 RENIN ACTIVITY ng/100 ml
300
The effect of acute administration of chlorpromazine on PRA, plasma aldosterone, and blood pressure was studied in 12 patients in the Neuropsychiatric ward. The nature of the study was fully explained to the patients and informed consent was obtained. All subjects were Caucasian and under the age of 40. Although some of them had been treated with phenothiazine antipsychotics in the past, none had received treatment for at least one week prior to the study. All subjects were on a diet consisting of 150 mEq of sodium. None of them was hypertensive or had any evidence of cardiovascular or renal disease. Because of the diurnal variation in PRA and aldosterone (3) all studies were conducted in the morning starting at 8 AM. On the day of the study, the subjects
900 RENIN ACTIVITY ng/100 ml 600
300
30
rfi Baseline
3°
60
120
20 ALDOSTERONE ng/100 ml 10
30
60
120
180
Baseline TIME IN MINUTES FOLLOWING 10 mg CHLORPROMAZINE ADMINISTRATION
FIG. 2. The effect of 10 mg of chlorpromazine upon plasma renin activity and aldosterone levels. All subjects were supine during the study. Results show mean ± SEM. remained supine from midnight until the completion of the study. They received breakfast at 6 AM. At 8 AM butterfly IV was placed on the right arm for infusion and blood sampling. At 8:30 AM and 8:45 AM, control blood samples were taken. At 9 AM the subjects were given either 25 or 10 mg of chlorpromazine slowly intravenously. Blood samples for PRA and aldosterone were then taken at 9:30, 10:00, 11:00 AM and 12:00 noon. These samples were thus taken 30,60,120, and 180 min after the administration of chlorpromazine. In all subjects, blood pressure was determined at specified intervals during the study. The PRA was measured by the radioimmunoassay method (16) and is reported in nanograms (ng) of angiotensin/100 ml of plasma generated during a 3h incubation period. Plasma aldosterone was measured by a method described elsewhere (17) and is expressed in ng/100 ml of plasma.
1200-
20
rfl
30-
Materials and Methods
ALDOSTERONE ng/100 ml
rti
Results 180
TIME IN MINUTES FOLLOWING 25 mg CHLORPROMAZINE ADMINISTRATION
FIG. 1. The effect of 25 mg of chlorpromazine upon plasma renin activity and aldosterone levels. All subjects were supine during the study. Results show mean ± SEM.
Effect of intravenous administration of 25 rag of chlorpromazine on PRA and aldosterone. Twenty-five mg of chlorpromazine was given to 5 patients. All subjects responded with a rise in PRA and aldosterone. The maximum rise in PRA from the control levels of 343 ± 60 (SEM) ng/100 ml to 1018 ± 160 (SEM) ng/100 ml occurred 60 min after chlorpromazine administration (Fig. 1).
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 21:21 For personal use only. No other uses without permission. . All rights reserved.
1168
COMMENTS
Subsequently the PRA declined until at 180 min it was 645 ± 120. Applying Student's t test to paired individual changes from control to the 60 minute sample revealed these changes to be significant at the 0.05 level. An average blood pressure decrease of 10/2 mm Hg was observed but was not statistically significant. In individual patients the changes in PRA did not bear close relationship to concomitant blood pressure recordings. Since patients remained supine throughout the study postural hypotension could not be observed. The plasma aldosterone levels tended to parallel the PRA levels with the maximum also at 60 min (Fig. 1). The rise in plasma aldosterone observed at 60 min was significant at the 0.05 level. Effect of intravenous administration of 10 mg of chlorpromazine on PRA and aldosterone. Ten mg of chlorpromazine was given to 7 patients. There were no changes in systemic blood pressure during the study. PRA rose in all patients studied (Fig. 2) but with the small sample size, levels of significance were not reached. However, the plasma aldosterone levels at 60 and 120 min after chlorpromazine were significantly elevated, as they had been with the 25 mg dose (Fig. 2). No changes in serum concentration of electrolytes were noted during these studies with either the 10 mg or 25 mg dosage. Discussion Renin secretion is affected by various endogenous and exogenous stimuli (18) and many drugs are known to act on the renin-angiotensinaldosterone system (1,3,6,10) both directly and indirectly. Now that the level of PRA may have therapeutic significance, it is important that the effects of commonly used drugs on renin and aldosterone be known in order to avoid misinterpretation of data used in the diagnosis of renal or adrenal abnormalities. The results of the present study indicate that chlorpromazine affects the renin-aldosterone system. The intravenous administration of chlorpromazine dramatically elevated plasma aldosterone levels and PRA, and the response of the aldosterone was as great with the 10 mg dose as with the 25 mg dose. All these changes occurred without significant change in systemic blood pressure or pulse. Since PRA is known to be increased by beta agonists, these findings are consistent with the hypothesis that chlorpromazine possesses some
JCE & M • 1975 Vol 41 • No 6
beta adrenergic activity. However, there are other possibilities that cannot be excluded. There could be PRA stimultion by a centrally mediated drug effect on the autonomic nervous system directly or via the adrenal medulla. Although the systemic blood pressure did not change, it is possible that there were local changes at the level of the renal baroreceptor or alterations in renal blood flow. Although no definite explanation for the elevated PRA and plasma aldosterone after chlorpromazine administration is offered, the magnitude of the change deserves consideration. With the increasing use of PRA and aldosterone to screen patients for possible renal and adrenal pathology, data on patients receiving phenothiazines may be misinterpreted as implying underlying pathology. Of great interest is the impressive stimulation of aldosterone found after the lower dose of chlorpromazine. The effects of chronic oral administration of chlorpromazine on the kidney and the adrenal cortex merit further investigation. References 1. Michelakis, A. M., J. Caudle, and G. W. Liddle,Proc Soc Exp Biol Med 130: 748, 1969. 2. Vander, A. J., Am J Physiol 209: 659, 1955. 3. Michelakis, A. M., and R. Horton, Circ Res (suppl) 27: 185, 1970. 4. Menzie, J., A. M. Michelakis, and H. Yoshida, AmJ Physiol 227: 1281, 1974. 5. Otsuka, K., T. Assaykeen, A. Goldfien, and W. F. Ganong, Endocrinology 187: 1306, 1970. 6. Assaykeen, T., P. L. Clayton, A. Goldfien, and W. F. Ganong, Endocrinology 187: 1318, 1970. 7. Passo, S. S., T. Assaykeen, K. Otsuka, B. L. Wise, A. Goldfien, and W. F. Ganong, Neuroendocrinology 7: 1, 1971. 8. Wise, B. L., and W. F. Ganong, Am J Physiol 198: 1291, 1960. 9. Gump, F. E., T. Magill, A. P. Thai, and J. M. Kinney, Surg Gynecol Obstet 127: 319, 1968. 10. Michelakis, A. M., and R. G. McAllister, J Clin Endocrinol Metab 34: 386, 1972. 11. Passo, S. S., T. Assaykeen, A. Goldfien, and W. F. Ganong, Neuroendocrinology 7: 97, 1971. 12. Moyer, J. H.J Clin Exp Psychopathol 16:179,1955. 13. Martin, W. R., J. L. Riehl, and K. R. UnnaJ Pharm Exp Ther 130: 37, 1960. 14. Gokhale, S. D., O. D. Gulati, and H. M. Parikh, BrJ Pharmacol 23: 508, 1964. 15. Webster, R. A., BrJ Pharmacol 25: 566, 1965. 16. Haber, E., T. Koerner, L. B. Page, B. Kliman, and A. PumodeJ Clin Endocrinol Metab 29: 1349, 1969. 17. Mayes, D., S. Furuyama, D. C. Kern, and C. A. Nugent, 7 Clin Endocrinol Metab 30: 682, 1970. 18. Vander, A. J., Physiol Rev 47: 359, 1967.
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