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Neuroendocrine Sources of Chromogranin-A in Normal Man: Clues from Selective Stimulation of Endocrine Glands^*

MARWAN A. TAKIYYUDDIN, 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
Albert Ludwigs Universitat Freiburg, West Germany

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.

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 1.7- and 14-fold rises in plasma CgA and epinephrine, respectively. 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.

^* This work was supported by the V.A., the NIH, the American Heart Association, and the National Kidney Foundation.

Fellow of the National Kidney Foundation.

Received January 12, 1990.

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