Are Human Adrenal Medullary Chromaffin Cells Adrenaline or Noradrenaline Cells? A Lesson Regarding the Importance of Understanding a Process to Reach a Conclusion
2025 Volume 47 Issue 1 Pages 1-4
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2025 Volume 47 Issue 1 Pages 1-4
A scientist may realize, during a long academic career, that a widely accepted notion is not actually factual. An example for me is the fraction of adrenaline-secreting cells in human adrenal medullary chromaffin (AMC) cells. Even the authoritative textbooks for medical physiology differ regarding the fraction of adrenaline cells in human AMC cells, stating that it is 80% or 100%. This confusion may be ascribed to the substitution of the fraction of adrenaline in the catecholamines extracted from the human adrenal medulla for the fraction of adrenaline cells in human AMC cells. In this commentary, I look into the possible cause of this substitution and highlight the importance of understanding a process to reach a conclusion.
A scientist may realize, during a long academic career, that a widely accepted notion is not actually factual. I have experienced this phenomenon regarding the fraction of adrenaline-secreting cells in human adrenal medullary chromaffin (AMC) cells. This story begins in 2017 in Sheffield, UK, at the 19th International Symposium of Chromaffin Cell Biology (ISCCB), which is held every 2 years [1]. One researcher gave a presentation about the immunohistochemistry of human adrenal medullae. She reported that all AMC cells are immunostained by an antibody against phenylethanolamine N-methyl transferase (PNMT), which catalyzes the conversion of noradrenaline to adrenaline. One of my acquaintances quickly raised his hand to comment on her presentation. He stated that, according to textbooks, adrenaline and noradrenaline cells represent 80% and 20% of the human AMC cells, respectively. At that time, I also believed that 20% of human chromaffin cells are noradrenaline cells and used to teach that to second-year medical students, so I was surprised by her results. Responding to my acquaintance’s comments, she stated that she could not find any references demonstrating the presence of noradrenaline cells in the human adrenal medulla.
The cell composition in the adrenal medulla varies depending on the animal species. Almost every chromaffin cell in rabbits and guinea pigs is an adrenaline cell, whereas 20% of rat and bovine adrenal chromaffin cells are noradrenaline cells [2, 3]. AMC cells and sympathetic ganglion cells are similar from the point of view of ontogenetics: both originate from the neural crest [4]. The neural crest cells that stop at the middle in the migratory process from the dorsal part to the ventral part differentiate into sympathetic ganglion cells, whereas those that enter the adrenal cortical anlage differentiate into AMC cells at the ventral part. It is not surprising, therefore, that AMC cells might use noradrenaline as a signal transmission factor. However, AMC cells are assumed to covey different information from that conveyed by the sympathetic nervous system [5]. If that is the case, then it is necessary to use a signal transmission factor that is different from what is used in the sympathetic nervous system. In this context, whether human AMC cells exclusively use adrenaline as a signal transmission factor has an important meaning.
Ganong’s Review of Medical Physiology (25th edition) states that almost every human AMC cell is an adrenaline cell [6], whereas Guyton and Hall Textbook of Medical Physiology (13th edition) states that 80% and 20% of human AMC cells are adrenaline and noradrenaline cells [7], respectively. Tank and Wong stated in their 2015 review that 80% and 20% of human AMC cells are adrenaline and noradrenaline cells [8], respectively. Thus, I tentatively propose two hypotheses: the 100% hypothesis states that almost all human AMC cells are adrenaline cells, and the 80% hypothesis states that 80% and 20% of the human AMC cells are adrenaline and noradrenaline cells, respectively. Readers might think that whether adrenaline cells constitute 100% or 80% of human AMC cells is not critical. However, 20% is biologically important, given that the adrenal medullary system develops in humans to convey information that is different from that of the sympathetic nervous system [5]. Consider that evolution is a process that makes life more efficient. Thus, an increase from 80% to 100% represents a 25% increase in efficiency.
I searched PubMed for references regarding the 100% and 80% hypotheses. I found only one reference, published in 1979, in support of the 80% hypothesis [9]. The authors stated that all cells in the human adrenal medulla are dopamine β-hydroxylase (DβH) positive and most cells are PNMT positive, suggesting that 10%–20% of the cells contain noradrenaline whereas the remainder contain adrenaline. The authors did not quantitatively analyze DβH and PNMT co-staining; instead, they cited a 1965 book by R.E. Coupland to support their notion [10].
Coupland was a prominent British anatomist who studied the adrenal medulla at the light and electron microscopic levels. The mammalian adrenal gland consists of the adrenal medulla at the core and the surrounding adrenal cortex, which mainly secrete catecholamines and steroid hormones, respectively. He elucidated the presence of the two vascular systems in the adrenal medulla: one system becomes a capillary in the adrenal cortex before entering the adrenal medulla; the other system enters the adrenal medulla without becoming a capillary in the adrenal cortex. He coined the term intra-adrenal portal vascular system for the former system [11]. This unique vascular system plays a pivotal role in the endocrine function of the adrenal medulla [12, 13]. Coupland stated that noradrenaline constitutes 5%–20% of the catecholamines in the human adrenal medulla and that the remaining catecholamines are adrenaline. He cited a few original papers [14], including his own, which stated that noradrenaline accounts for 10%–25% of the catecholamines in the human adrenal gland after the age of 3 years [15]. What is important about these papers is that the authors measured the fraction of adrenaline in the catecholamines extracted from the adrenal medulla.
The 100% hypothesis is based on the measurement of the fraction of adrenaline cells in human AMC cells. Noradrenaline and adrenaline cells are identified as cells with noradrenaline- and adrenaline-containing chromaffin granules, respectively, at the electron microscopic level. Noradrenaline granules appear as eccentrically located electron-dense material; there is a clear space between the granule membrane and the electron-dense material. On the other hand, adrenaline granules are completely filled with less electron-dense material [16]. The cytoplasm in AMC cells in adult animals is filled with either adrenaline or noradrenaline granules and not a mixture of the two [17]. At the light microscopic level, adrenaline is detected in cells containing both DβH- and PNMT-like immunoreactive material, whereas noradrenaline cells lack PNMT-like immunoreactivity. In addition, adrenaline and noradrenaline cells secrete only adrenaline and noradrenaline, respectively, through exocytosis in response to secretagogues [18, 19]. Thus, the fraction of adrenaline cells is estimated by measuring the fraction of adrenaline in adrenal venous blood. These three lines of evidence consistently support the 100% hypothesis [20–23]. What is the cause of the different conclusions? Coupland and others measured the fraction of adrenaline in the catecholamines extracted from the human adrenal medulla, but not the fraction of adrenaline cells.
It is worth noting that noradrenaline could be present in the cytosol as well as secretary granules. Tyrosine is transformed to L-dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase and then to dopamine by L-aromatic amino acid decarboxylase in the cytosol. Dopamine is taken up into the chromaffin granules through the vesicular monoamine transporter (VMAT) and transformed to noradrenaline by DβH. Noradrenaline is transported to the cytosol, where it is converted to adrenaline by PNMT. Adrenaline is then taken up into the chromaffin granules by VMAT. Thus, adrenaline cells are assumed to contain adrenaline in the chromaffin granules and noradrenaline in the cytosol [19]. Secretion occurs through exocytosis of the chromaffin granules. Therefore, adrenaline in the catecholamines in the adrenal venous blood originates from adrenaline cells. Of note, the fraction of adrenaline in adrenal catecholamines might not be equal to that of adrenaline cells. In fact, in stimulated cat adrenal medullae, the fraction of adrenaline in the adrenal venous blood was consistently higher than that in the adrenal catecholamines [23], but there was a different finding in the rat adrenal medulla: the fraction of adrenaline in the blood catecholamines was the same as that in the adrenal catecholamines [17]. Thus, the relative amount of noradrenaline present in adrenaline cells might vary in mammals: certain mammals might have a relatively high amount of noradrenaline in adrenaline cells.
The confusion regarding the fraction of adrenaline cells in the human AMC cells seems to originate from the substitution of the fraction of adrenaline with that of adrenaline cells. How did this substitution occur? Douglas W.W. and his colleague elucidated in 1961 that membrane excitation in cat adrenal medullae induced catecholamine secretion in a Ca2+-dependent manner and named the phenomenon excitation-secretion coupling [24]. Electron microscopy revealed that secretion occurs through exocytosis of secretary granules [18], and adrenaline and noradrenaline are stored in separate secretory granules [16]. These studies lead to the notion that adrenaline and noradrenaline are secreted from two different types of AMC cells. Furthermore, adrenaline and noradrenaline cells are innervated differently by the central nervous system. Noradrenaline cells are activated in a reflex manner in response to a decrease in blood pressure [25], as are the sympathetic ganglion cells. On the other hand, adrenaline cells are preferentially activated by hypoglycemia [26]. With the progress in AMC cell research, the focus has been directed to adrenaline cells rather than adrenaline. As a result, researchers have probably substituted the fraction of adrenaline with the fraction of adrenaline cells. Researchers who have been engaged in chromaffin cell research for a quite long time may fall into this trap. This issue regarding the fraction of adrenaline cells highlights the need to recognize the importance of understanding a process to reach a conclusion.
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Data sharing is not applicable to this article as no new data were created or analyzed in this study.
I appreciate Dr. K. Harada and Ms. Oouchi for sharing the book by Coupland.
