Study Questions NPB 130 Lecture 19: Adrenal Medulla and Catecholamines

Study Questions for NPB 130, Autumn 2025 Lecture 19: Adrenal Medulla and Catecholamines (29 October)

1. Relationship of Adrenal Medulla to the Sympathetic Nervous System

  • The adrenal medulla is essentially an organ of the sympathetic nervous system that functions as an endocrine gland.
  • It synthesizes and secretes catecholamines, primarily epinephrine and norepinephrine, which are involved in the body's stress response.
  • The adrenal medulla acts as a 'modified sympathetic ganglion', where the chromaffin cells work similarly to post-ganglionic neurons by releasing hormones into the bloodstream instead of synaptic messages to target organs.

2. Post-Ganglionic Neurons of the Sympathetic Nervous System

  • Post-ganglionic neurons are neurons that receive signals from pre-ganglionic neurons, which originate in the spinal cord.
  • These neurons send nerve impulses to various target organs.
  • The neurotransmitter released by these post-ganglionic neurons is primarily norepinephrine in most cases, but acetylcholine can also be released by those innervating sweat glands.

3. Chromaffin Cells and Hormones They Release

  • Chromaffin cells are specialized cells in the adrenal medulla that release catecholamines: epinephrine (adrenaline) and norepinephrine (noradrenaline).
  • These cells are derived from neural crest cells and are responsible for the endocrine aspects of the sympathetic nervous system.

4. Similarities and Differences between Chromaffin Cells and Post-Ganglionic Neurons

  • Similarities:
    • Both chromaffin cells and post-ganglionic neurons are part of the sympathetic nervous system and are involved in the body's fight-or-flight response.
    • They both respond to stimulation from the sympathetic nervous system and release catecholamines (in the case of chromaffin cells) or neurotransmitters (in post-ganglionic neurons).
  • Differences:
    • Chromaffin cells secrete hormones directly into the bloodstream, while post-ganglionic neurons release neurotransmitters at synaptic junctions.
    • The primary neurotransmitter for post-ganglionic neurons is norepinephrine, while chromaffin cells predominantly release epinephrine.

5. Stimulation of Adrenal Medullary Hormone Release

  • Adrenal medullary cells release hormones mainly in response to neural signals from pre-ganglionic sympathetic fibers, specifically from the thoracic spinal cord.
  • The sympathetic stimulation causes these cells to release catecholamines into the bloodstream, enhancing the body's fight-or-flight response.

6. Catecholamines: Types and Synthesis Sequence

  • The three primary catecholamines are:
    1. Dopamine
    2. Norepinephrine
    3. Epinephrine
  • They are synthesized from the amino acid tyrosine, which is the original precursor. The sequence of production is:
    1. Tyrosine → Dihydroxyphenylalanine (DOPA, via the enzyme tyrosine hydroxylase)
    2. DOPA → Dopamine (via DOPA decarboxylase)
    3. Dopamine → Norepinephrine (via dopamine β-hydroxylase)
    4. Norepinephrine → Epinephrine (via phenylethanolamine N-methyltransferase, PMNT)

7. Preventing Sympathetic Post-Ganglionic Neurons from Releasing Epinephrine

  • The reason sympathetic post-ganglionic neurons do not release epinephrine is that they lack the enzyme phenylethanolamine N-methyltransferase (PMNT), which is crucial for converting norepinephrine to epinephrine.
  • Thus, while norepinephrine is the primary neurotransmitter released in synapses by post-ganglionic neurons, chromaffin cells of the adrenal medulla predominantly secrete epinephrine into the bloodstream.

8. Effects of Glucocorticoids on Catecholamine Synthesis

  • Glucocorticoids, such as cortisol, enhance the synthesis of catecholamines in adrenal medullary cells through the induction of specific enzymes.
    • (a) Cortisol induces the enzyme phenylethanolamine N-methyltransferase (PMNT) in adrenal medullary cells, facilitating the conversion of norepinephrine to epinephrine.
    • (b) The anatomical organization of the adrenal gland facilitates glucocorticoids impacting medullary cells due to a rich blood supply that originates from the adrenal cortex, allowing efficient delivery of hormones to the medulla.
    • (c) Adrenal medullary cells do have glucocorticoid receptors, indicating that the effects of ACTH (Adrenocorticotropic hormone) and glucocorticoids on chromaffin cells are direct. However, they do not express MC2R receptors.

9. Proportions of Hormone Secretion from the Adrenal Medulla

  • Approximately 80% of hormone secretion from the adrenal medulla consists of epinephrine.
  • The remaining 20% consists of norepinephrine.
  • The majority of the norepinephrine circulating in the blood during a major sympathetic nervous activation event typically comes from post-ganglionic neurons, not the adrenal medulla.

10. Catecholamine Release and Situational Triggers

  • Catecholamine release does not only occur during acute stress or “fight or flight” situations; substantial sympathetic activation can occur under chronic stress or other physiological conditions.
  • An example illustrating this is during prolonged exercise, where catecholamine levels can remain elevated to sustain metabolic increases and maintain cardiovascular function.

11. Interaction Between Epinephrine and Glucocorticoids on Adipocytes and Hepatocytes

  • Epinephrine stimulates lipolysis in adipocytes, leading to the breakdown of fats into free fatty acids, supporting energy production.
  • Concurrently, glucocorticoids enhance gluconeogenesis in hepatocytes, stimulating the formation of glucose to utilize for energy during stress.
  • This interaction increases overall energy availability.

12. Comparison of Effects on Gluconeogenesis and Glycogenesis/Glycogenolysis

  • (a) Both epinephrine and cortisol promote gluconeogenesis while inhibiting glycogenesis.
  • (b) In terms of glycogenolysis, epinephrine stimulates it, whereas glucocorticoids also enhance gluconeogenesis but do not directly affect glycogen breakdown.
  • Logic of Effects: Epinephrine acts quickly for immediate energy release, while glucocorticoids modulate long-term energy management, resulting in complementary roles without being in conflict.

13. Relative Importance of Epinephrine vs. Norepinephrine

  • In the regulation of:
    1. Cardiac Effects: Epinephrine has a more significant role in increasing heart rate and stroke volume.
    2. Vascular Tone: Norepinephrine primarily regulates vascular tone through vasoconstriction driven by sympathetic activation, but epinephrine can induce vasodilation in certain vascular beds.
    3. Metabolic Effects: Both are crucial, but epinephrine enhances metabolic effects via glycogenolysis and gluconeogenesis more potently than norepinephrine.

14. Types of Adrenergic Receptors and Membrane Receptor Class

  • There are 5 main types of adrenergic receptors:
    1. Alpha-1 (α1)
    2. Alpha-2 (α2)
    3. Beta-1 (β1)
    4. Beta-2 (β2)
    5. Beta-3 (β3)
  • These receptors belong to the general class of G protein-coupled receptors (GPCRs), which mediate cellular responses when activated by catecholamines.
14a. Subclasses of Membrane Receptors in Catecholamine Responses
  • The three subclasses of GPCRs involved in cellular responses to catecholamines include:
    1. α1-adrenergic receptors (excitatory response)
    2. α2-adrenergic receptors (inhibitory response)
    3. β-adrenergic receptors (generally excitatory response)

15. Affinities of Adrenergic Receptors for Catecholamines

  • The different adrenergic receptors show varying affinities for epinephrine and norepinephrine, impacting physiological responses:
    • (a) Differences in affinity mean that certain receptors can bind both catecholamines, but they may respond differently based on receptor type and concentration level.
    • (b) At low concentrations of hormone, receptors with high affinity for one catecholamine will more likely be occupied, while high concentrations will saturate more receptors, allowing low-affinity receptors to participate.
    • Specific Examples:
      1. Low epinephrine, low norepinephrine - α1 binds norepinephrine, β2 may remain unbound.
      2. Low epinephrine, high norepinephrine - α1 receptors are occupied by norepinephrine, β2 may still be unbound or less fully activated.
      3. High epinephrine, low norepinephrine - α1 may be fully occupied, β2 may also start binding epinephrine, leading to mixed effects.
      4. High epinephrine, high norepinephrine - At saturation level, both receptors bind epinephrine leading to strong vasoconstriction (from α1) and potential vasodilation (from β2).
    • (c) Higher concentrations of circulating epinephrine can shift the effects from vasodilatory to vasoconstrictory due to preferential binding to lower affinity α1 receptors over β2 receptors as epinephrine levels increase.

16. Physiological Responses to Circulating Epinephrine

  • The three factors that determine the physiological response to circulating epinephrine include:
    1. The concentration of epinephrine in circulation.
    2. The type of adrenergic receptors present on target cells.
    3. The specific signal transduction pathways activated by receptor binding, which leads to varied physiological outcomes.

17. Integration of Adrenergic and Adrenocortical Control of Metabolic Processes in the Liver

  • During the Alarm Phase (Fight or Flight): Elevated epinephrine promotes glycogen mobilization and inhibits glycogen synthesis to provide immediate glucose for energy demands.
  • During the Resistance Phase: Glucocorticoids lead to enhanced gluconeogenesis and maintain blood sugar levels, thereby supporting energy production over prolonged periods.
  • The effects of these hormones are not in conflict; instead, they are complementary and adaptive, working together to manage energy during stress effectively.