0021-972X/90/7102-0360$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society
Vol. 71, No. 2 Printed in U.S.A.
Neuroendocrine Sources of Chromogranin-A in Normal Man: Clues from Selective Stimulation of Endocrine Glands* MARWAN A. TAKIYYUDDINf, JUSTINE H. CERVENKA, M. R. PANDIAN, CYNTHIA A. STUENKEL, HARTMUT P. H. NEUMANN, AND DANIEL T. O'CONNOR Departments of Medicine and Reproductive Medicine, University of California, and the Veterans Administration Medical Center, San Diego, California 92161; and Albert Ludwigs Universitat, Freiburg, West Germany
However, insulin-induced hypoglycemia failed to perturb plasma CgA in three bilaterally adrenalectomized patients, suggesting that the adrenal medulla is the source of plasma CgA elevation during hypoglycemia in normal subjects. Cell type-selective secretagogue stimulation of normal endocrine secretory cells other than the adrenal medulla (pituitary, pancreas, gut, thyroid, and parathyroid) induced measurable increments in the concentrations of the resident peptide hormones, but left plasma CgA unperturbed. Nonselective stimulation of a wide variety of endocrine secretory cells with pentagastrin elevated plasma CgA 1.4-fold. However, restriction of pentagastrin's targets by coinfusion of calcium abolished the effect on plasma CgA. Hence, within the normal human neuroendocrine system, only selective stimulation of the adrenal medulla is likely to elevate plasma CgA under physiological or pharmacological circumstances. This is consistent with our finding of the adrenal medulla as the quantitatively major normal neuroendocrine tissue source of CgA immunoreactivity. (J Clin Endocrinol Metab 7 1 : 360-369, 1990)
ABSTRACT. Chromogranin-A (CgA), as measured in the circulation by RIA, has emerged as a useful probe of exocytotic sympathoadrenal activity in man as well as of the presence and extent of neuroendocrine neoplasia. Here we studied, using a sensitive RIA, the distribution of CgA immunoreactivity in normal human neuroendocrine tissues. Furthermore, to investigate whether these normal tissue sources measurably contribute to plasma CgA, we measured plasma CgA, catecholamine, and other polypeptide hormone responses to selective stimuli of secretion at several sites within the neuroendocrine system. Immunoreactive CgA was ubiquitous in human neuroendocrine tissues, in rank order of concentration (micrograms per g wet wt): adrenal medulla > pituitary > pancreas > stomach > small intestine (jejunoileum) > brain (frontal cortex) > parathyroid > thyroid. Quantitatively, neuroendocrine tissues other than the adrenal medulla possessed only 0.04-25% of the immunoreactivity found in the adrenal medulla. Insulin-induced hypoglycemia, a potent stimulus of adrenomedullary secretion, resulted in 1.7and 14-fold rises in plasma CgA and epinephrine, respectively.
C
docrine tumors (10-15); thus, its elevated plasma concentration has emerged as a useful adjunct in the evaluation of such tumors (11, 16, 17). Of the many potential normal endocrine sources of CgA, which also measurably contribute to plasma CgA? To explore this question, we measured not only tissue concentrations of CgA, but also perturbations of plasma CgA along with several peptide hormones and catecholamines in response to selective secretagogues known to stimulate different normal neuroendocrine cell types. Our findings provide insight into the tissue sources that could contribute to variations in plasma CgA levels in normal subjects without neuroendocrine tumors.
HROMOGRANIN-A (CgA), originally described as a soluble protein stored with catecholamines in adrenal medullary and sympathetic neuronal vesicles (13), is coreleased with catecholamines into the bloodstream during sympathoadrenal activation in experimental animals (4) and man (5). Recently, CgA has been found in a widespread distribution in secretory vesicles throughout the neuroendocrine system, as demonstrated by RIA, immunoblotting, and immunohistology (6-9). In addition, CgA is secreted by a variety of neuroen-
Received January 12, 1990. Address all correspondence and requests for reprints to: Marwan A. Takiyyuddin, M.D., Nephrology/Hypertension (111H), Veterans Administration Medical Center, 3350 La Jolla Village Drive, San Diego, California 92161. * This work was supported by the V.A., the NIH, the American Heart Association, and the National Kidney Foundation. t Fellow of the National Kidney Foundation.
Materials and Methods The study group consisted of 75 healthy volunteers, 3 bilaterally adrenalectomized patients, and 20 pregnant females; they were 27-52 yr old. The studies were approved by the University 360
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 17 November 2015. at 15:34 For personal use only. No other uses without permission. . All rights reserved.
CgA RELEASE FROM NORMAL ENDOCRINE SOURCES
361
150
* Insulin, 0.15 units/Kg, IV
I Insulin, 0.15 units/kg, IV
Blood Glucose, mg/dL (A
8 _ 100 Chromogranin A, ng/ml
T> E o m
Eplnephrlne, pg/ml
Vol. 71, No. 2 Printed in U.S.A.
Neuroendocrine Sources of Chromogranin-A in Normal Man: Clues from Selective Stimulation of Endocrine Glands* MARWAN A. TAKIYYUDDINf, JUSTINE H. CERVENKA, M. R. PANDIAN, CYNTHIA A. STUENKEL, HARTMUT P. H. NEUMANN, AND DANIEL T. O'CONNOR Departments of Medicine and Reproductive Medicine, University of California, and the Veterans Administration Medical Center, San Diego, California 92161; and Albert Ludwigs Universitat, Freiburg, West Germany
However, insulin-induced hypoglycemia failed to perturb plasma CgA in three bilaterally adrenalectomized patients, suggesting that the adrenal medulla is the source of plasma CgA elevation during hypoglycemia in normal subjects. Cell type-selective secretagogue stimulation of normal endocrine secretory cells other than the adrenal medulla (pituitary, pancreas, gut, thyroid, and parathyroid) induced measurable increments in the concentrations of the resident peptide hormones, but left plasma CgA unperturbed. Nonselective stimulation of a wide variety of endocrine secretory cells with pentagastrin elevated plasma CgA 1.4-fold. However, restriction of pentagastrin's targets by coinfusion of calcium abolished the effect on plasma CgA. Hence, within the normal human neuroendocrine system, only selective stimulation of the adrenal medulla is likely to elevate plasma CgA under physiological or pharmacological circumstances. This is consistent with our finding of the adrenal medulla as the quantitatively major normal neuroendocrine tissue source of CgA immunoreactivity. (J Clin Endocrinol Metab 7 1 : 360-369, 1990)
ABSTRACT. Chromogranin-A (CgA), as measured in the circulation by RIA, has emerged as a useful probe of exocytotic sympathoadrenal activity in man as well as of the presence and extent of neuroendocrine neoplasia. Here we studied, using a sensitive RIA, the distribution of CgA immunoreactivity in normal human neuroendocrine tissues. Furthermore, to investigate whether these normal tissue sources measurably contribute to plasma CgA, we measured plasma CgA, catecholamine, and other polypeptide hormone responses to selective stimuli of secretion at several sites within the neuroendocrine system. Immunoreactive CgA was ubiquitous in human neuroendocrine tissues, in rank order of concentration (micrograms per g wet wt): adrenal medulla > pituitary > pancreas > stomach > small intestine (jejunoileum) > brain (frontal cortex) > parathyroid > thyroid. Quantitatively, neuroendocrine tissues other than the adrenal medulla possessed only 0.04-25% of the immunoreactivity found in the adrenal medulla. Insulin-induced hypoglycemia, a potent stimulus of adrenomedullary secretion, resulted in 1.7and 14-fold rises in plasma CgA and epinephrine, respectively.
C
docrine tumors (10-15); thus, its elevated plasma concentration has emerged as a useful adjunct in the evaluation of such tumors (11, 16, 17). Of the many potential normal endocrine sources of CgA, which also measurably contribute to plasma CgA? To explore this question, we measured not only tissue concentrations of CgA, but also perturbations of plasma CgA along with several peptide hormones and catecholamines in response to selective secretagogues known to stimulate different normal neuroendocrine cell types. Our findings provide insight into the tissue sources that could contribute to variations in plasma CgA levels in normal subjects without neuroendocrine tumors.
HROMOGRANIN-A (CgA), originally described as a soluble protein stored with catecholamines in adrenal medullary and sympathetic neuronal vesicles (13), is coreleased with catecholamines into the bloodstream during sympathoadrenal activation in experimental animals (4) and man (5). Recently, CgA has been found in a widespread distribution in secretory vesicles throughout the neuroendocrine system, as demonstrated by RIA, immunoblotting, and immunohistology (6-9). In addition, CgA is secreted by a variety of neuroen-
Received January 12, 1990. Address all correspondence and requests for reprints to: Marwan A. Takiyyuddin, M.D., Nephrology/Hypertension (111H), Veterans Administration Medical Center, 3350 La Jolla Village Drive, San Diego, California 92161. * This work was supported by the V.A., the NIH, the American Heart Association, and the National Kidney Foundation. t Fellow of the National Kidney Foundation.
Materials and Methods The study group consisted of 75 healthy volunteers, 3 bilaterally adrenalectomized patients, and 20 pregnant females; they were 27-52 yr old. The studies were approved by the University 360
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 17 November 2015. at 15:34 For personal use only. No other uses without permission. . All rights reserved.
CgA RELEASE FROM NORMAL ENDOCRINE SOURCES
361
150
* Insulin, 0.15 units/Kg, IV
I Insulin, 0.15 units/kg, IV
Blood Glucose, mg/dL (A
8 _ 100 Chromogranin A, ng/ml
T> E o m
Eplnephrlne, pg/ml
