Figure 1: Molecular model of epinephrine (From World of Molecules.)Epinephrine is a catecholamine, released from the adrenal gland, and a vital hormone in the short term stress response, or the fight or flight response as it is more commonly known. This state was initially described by Walter Cannon, an American physiologist, in 1915. The theory he developed states that animals react to cases of acute stress by a generalized discharge of the sympathetic nervous system. This, in turn, prepares the animal to fight or flee [1].
Normally animals maintain homeostasis, another state described by Walter Cannon in which a constant internal environment is maintained in lieu of changes in the external environment. In this state, the neurons in the locus ceruleus (a nucleus in the brain stem involved with the stress response; see photo to the right, from MindBlog) fire in regular intervals [1, 3, 4]. When a stressful stimulus is perceived, a signal is relayed from the sensory cortex of the brain via the hypothalamus to the brain stem. This signaling route increases the rate of noradrenergic activity in the locus ceruleus. This increase in activity causes a corresponding increase in alertness in the organism. Catecholamines are released and their abundance at the locus ceruleus neuroreceptors facilitate behaviors related to combat or escape [3, 4].
A different sort of response occurs when the stimulus is perceived as a threat. A signal is still relayed from the sensory cortex of the brain via the hypothalamus to the brain stem, but it is a more intense and prolonged discharge [3]. This then activates the sympathetic division of the autonomic nervous system. Acetylcholine release is triggered from preganglionic sympathetic nerves which then triggers a release of epinephrine from the chromaffin cells in the medulla of the adrenal glands [3, 4]. The epinephrine causes a boost in the oxygen and glucose delivered to the brain and muscle as well as an increase in heart rate and stroke volume. It suppresses both the immune system and non-emergency bodily systems, such as the gastrointestinal tract [4].
Epinephrine acts through non selective binding of α1, α2, β1, and β2 adrenergic receptors on the cell plasma membrane. In the liver it binds the α1 receptors and starts the inositol-phospholipid signaling pathway [4]. This signals the phosphorylation of glycogen synthase, inactivating it, and phosphorylase kinase, activating it [3, 4]. The activation of phosphorylase kinase activates another enzyme called glycogen phosphorylase, which catalyzes the breakdown of glycogen. Glucose is then released into the bloodstream. β2 receptors are primarily found in skeletal muscle blood vessels and activation of these receptors causes vasodilation. In contrast, α adrenergic receptors are found in most smooth muscles cause vasoconstriction when activated by epinephrine [4, 5].
Figure 2: The Role of Epinephrine in the Fight or Flight Response (from Fight nor Flight).Effects caused by epinephrine in the fight or flight response include:
- Acceleration of heart rate and ventilation rate
- Inhibition of stomach and intestinal action
- Constriction of blood vessels
- Liberation of nutrients for muscular action
- Inhibition of lacrimal gland and inhibition of salivation
- Dilation of pupils
- Relaxation of bladder
- Inhibition of erection
- Auditory exclusion
- Tunnel vision [3, 4]
Related Pathology: Anaphylaxis
Anaphylactic shock is an allergic reaction that is classified as a Type I hypersensitivity reaction. The reaction may involve the skin, eyes, bronchopulmonary tissues and gastrointestinal tract and can result in death. After an initial exposure to the allergen, a person's immune system becomes sensitized to that allergen. On subsequent exposures, an allergic reaction occurs [2].
Figure 3: Type I Hypersensitivity Reaction (from The University of South Carolina School of Medicine.)This reaction is mediated by IgE antibodies while the primary cell component is the mast cell. Mast cells are found in connective tissue throughout the body, and in especially high concentrations in areas that are vascularized [2, 3]. In their cytoplasm are large granules which store chemical compounds, the most important of which are histamine and tumor necrosis factor-α (TNF-α). Histamine is an amine which causes dilation of local blood vessels and smooth muscle contraction while TNF-α causes vasodilation and further promotes the inflammatory response [2].
Figure 4: Activation of the Mast Cell in the Anaphylactic Response (from Davidson College.)
Figure 5: Chemical Factors Released by Mast Cells During Anaphylaxis (from Davidson College.)When a person is exposed to a certain allergen, IgE antibodies are preferentially produced. IgE has a very high affinity for its receptor on mast cells [2]. Subsequent exposures to the same allergen cross links the cell-bound IgE and triggers the release of chemical substances, or degranulation. These substances include histamine (causing bronchoconstricion, mucus secretion, vasodilation, and vascular permeability), tryptase (causing proteolysis), and prostoglandins (causing edema and pain) [2].
These substances enter circulation and have a profound system wide effect, and cause systematic vasodilation (associated with a sudden drop in blood pressure) and edema of bronchial mucosa (resulting in bronchoconstriction and difficulty breathing) [2]. If left untreated, anaphylactic shock can lead to death in a matter of minutes [2].
Treatment
Figure 6: Epinephrine for treatment of anaphylaxis. (From VaxServe.)Primary treatment of anaphylaxis is epinephrine [2, 4]. Epinephrine prevents worsening of the airway constriction and stimulates the heart to continue beating by binding non selectively to α1, α2, β1, and β2 adrenergic receptors on the cell plasma membrane [4].
Epinephrine helps control the relaxation and contraction of smooth muscle cells.
Muscle contraction occurs through binding of calmodulin to calcium ions. Contractions in smooth muscle are initiated by chemicals that increase the levels of intracellular calcium. The calcium then binds with calmodulin, which then binds to and activates myosin-light chain kinase. This complex then phosphorylates myosin and activates the myosin ATPase. This causes the muscle to contract [4]. When epinephrine binds to an epinephrine receptor it activates adenylyl cyclase, which produces cyclic AMP (cAMP) from ATP. Then cAMP acticates a protein kinase, which phosphorylates myosin light chain kinase. Phosphorylation inactivates this kinase so it has a lower affinity for the calcium-calmodulin complex. This stops the downstream signal for muscle contraction. This relaxed the smooth muscle tissue. Epinephrine also decreases the release and membrane permeability of histamine to reduce the effects of histamine [6].
Epinephrine helps raise blood pressure.
To raise blood pressure, epinephrine binds β-adrenergic receptors, which change shape and activate G-Proteins, which activate adenylyl cyclase to convert ATP to cAMP [4]. cAMP activates cAMP-dependent protein kinase (PKA) [4]. In cardiac muscle, PKA phosphorylates calcium channels in the plasma membrane and myosin heads [4, 7]. Phosphorylated calcium channels remain open longer and thus allow more calcium into the myocardial cell. This, in turn, allows more myosin-binding sites on actin to be uncovered. More cross bridges can be formed, allowing for a stronger contractile force and a higher blood pressure [7].
Figure 7: Mechanism of Action of Epinephrine on Muscle Contraction During Anaphylaxis (from Davidson College.)Most people who have an allergy severe enough to cause anaphylaxis carry a d
ose of epinephrine with them at all times. Typically, this is in the form of an EpiPen (see photo on right; from Wikipedia). This small device will, when used, inject enough epinephrine into the casualty to give approximately 15 to 20 minutes of relief from the symptoms of anaphylaxis [2, 4]. This is usually enough time for the casualty to be taken to the hospital for further treatment. It is worthwhile to note that the effects of epinephrine are only a temporary relief from anaphylaxis and that further treatment is required. In a hospital setting, physicians aim to treat the cell hypersensitivity as well as the symptoms. Antihistamine drugs are given as well as corticosteroids. The hypotension is treated with intravenous fluids while bronchospasms are treated with bronchodilators [2].Epinephrine Overdose
An interesting side effect of the increased employment of EpiPens is a rise in the number of epinephrine overdoses. This often occurs when a helpful civilian is attempting to use an EpiPen (or similar device) on a casualty suffering from anaphylaxis and mistakenly injects him- or herself with the drug. Symptoms, including intense vasoconstriction leading to tissue ischemia and tachycardia, appear within seconds or minutes of injection [3, 4]. If treated promptly with phentolamine, a drug which causes vasodilation, recovery is usually swift with no lasting effects [5].
References
[1] Donnerer, Josef and Lembeck, Fred. (2006). The Chemical Languages of the Nervous System: History of Scientists and Substances. Basel, Switzerland: Reinhardt Druck.
[2] Kindt, T., Goldsby, R., Osborne, B. (2007). Kuby Immunology.New York, NY: W. H. Freeman and Company.
[3] Norris, David O. (2007). Vertebrate Endocrinology. Burlington, MA, USA: Elsevier Academic Press.
[4] Silverthorn, D. (2007). Human Physiology: An Integrated Approach. San Francisco, USA: Benjamin Cummings.
[5] Stolk, Jon M., U’Prichard, David C., Fuxe, Kjell. (Eds.). (1988). Epinephrine in the Central Nervous System. Oxford: Oxford University Press.
[6] Witcher, R. (2006). Anaphylaxis. Accessed November 4, 2008 http://www.bio.davidson.edu/courses/immunology/Students/spring2006/Witcher/Anaphylaxis.html
