Saturday, March 09, 2013

1893-1933: How does epinephrine (adrenaline) work? x

After epinephrine (adrenaline) was isolated in 1901 the quest continued to find better medicines from hormones for asthma and other diseases.  Almost as important was the quest to  to learn about how these medicines worked once they entered the body, and how to synthesize them.  While slow getting off, the quest ultimately lead to the medicines available to us today.  

The adrenal gland, which sits atop the kidneys, controls the autonomic nervous system, which is responsible for all the things inside your body you do not directly control by yourself. It gets its name from adrenaline, one of the hormones it produces. 

The autonomic nervous system has two divisions: 
  • Sympathetic: It reacts to stressful situations in your life, and is often referred to as flight or fright.  For example, if someone points a gun to your head, your adrenal gland increases hormones that cause vasoconstriction. This causes your heart rate to increase in rate and force, resulting in an increase in blood pressure. It also dilates your bladder so you don't pee your pants. It also causes bronchodilation so you can breathe deeper. 
  • Parasympathetic: It basically does just the opposite, and acts as a thermostat to turn your body functions back to normal.  For example, the gun now unloaded, your adrenal gland increases hormones that cause vasodilation. This causes your heart rate to decrease in rate and force, resulting in a decrease in blood pressure. It has a calming effect on your body. 

The basic anatomy of the adrenal gland and its effect on the sympathetic nervous system was understood by the middle of the 19th century. (6, page 5)  It was from this gland that various physicians in the last few years of the 19th century extracted hormones to perform experiments to learn what effect they caused. They tested the extracts on animals, on patients who volunteered, on their own children, and on themselves. 

Once they realized the vasoconstricting qualities of adrenal extracts, they tested it on various diseases, like hay fever and allergies. They did not know why it made breathing easier, although the initial theory was that asthma was caused by vasodilation that caused blood to congest in the chest. So the vasoconstricting properties of the extracts would relieve this congestion, making breathing easier.

Further testing found this theory to be false, that epinephrine mimics the sympathetic nervous system, and that it makes breathing easier because of it's bronchodilating qualities. It attaches to beta 2 receptors lining smooth muscles lining airways, and causes them to relax. This results in bronchodilation, making airways open. This made breathing easier, and it worked fast, particularly if injected. 

Later norepinephrine (noradrenaline) was isolated.

From here various experiments were performed and conclusions drawn.  Among the first was by John Newport Langley in 1901, who noticed that extracts containing epinephrine and norepinephrine caused a reaction similar to "sympathetic nerve stimulation." (1) 

In 1904  Thomas Rendon Elliot (1877-1961), working in Langley's laboratory, postulated the idea that a "chemical stimulant" was released when a nerve impulse was sent to a nerve synapse.  A nerve synapse is the space between a nerve and a muscle, and Elliot believed a chemical stimulant released by the synapse allowed an impulse to travel from the brain to that muscle cell.  (2)(6, page 65)  Then, in 1905, Langley postulated that adrenaline acted as such a "chemical stimulant." (2)

British Pharmacologist Henry Dale (1875-1968), who reported use of adrenaline as an inhalent, coined the term "sympathiomimetic amine" in reference to medicines like adrenaline that mimic the sympathetic nervous system's response, and in 1907 Paul Erlich came up with the idea that hormones that act as neurotrasmitters (such as epinephrine, norepindrugs and the drugs that mimic them) bind to receptors that sit on cells along vessels and smooth muscle, and he called these receptors chemoreceptors.(2)

Elliot ended up dropping his research to go back into clinical training due to "lack of interest in his work exhibited by the elite by the scientific establishment." Dale and Langley did not persue it, and Langley went as far as to note lack of interest because he didn't like to persue "speculative theories." (2)

In 1907 Cambridge Pharmacologist Walter Dixon "extended Elliots findings by arguing that parasympathetic nerves similarly liberate a neurotransmitter to activate effector sites" (sites where the receptors sit along smooth muscle and vessels) through the synaptic space between a nerve and the effector site.  (2)

Dale later hypothesized that the neurotransmitter Dixon wrote about was probably choline.  It was ultimately learned that medicines like Atropine, strammonium, and belladonna block the effects of choline, and were therefore referred to as anticholinergic.  Strammonium and Belladonna were already used for thousands of years for their hallucinogenic effect and to make breathing easier. Atropine was used since the early 19th century for breathing and to increase heart rate.  Now physicians knew why these drugs work. (2)

Yet the work of Elliot, Langley, Dixon and Dale was ultimately stalled due to both lack of interest by the scientific community and due to "limitations in methodology" that made it "difficult, if not impossible, to employ a more direct experimental approach to the problem at this time.  However, Elliot, Dixon and Hunt did not possess the burning interest and passion needed to overcome the obstacles presented by this fundamental biological problem."

It would be another 15  years before this line of research was picked up again. (2) So this is yet another example of the medical community initially ignoring something that would revolutionize the medical profession.  The profession had also initially rejected the watch, the germ theory, and the stethoscope)

In 1920 Otto Loewi came up with an idea to prove the the works of the above men.   (2) Loewi placed two frog hearts into a single bath, the vagus nerve of one heart was stimulated, thereby slowing it, while causing the rate of the second heart to also diminish. From this experiment, Loewi reached the conclusion that a substance liberated from the first heart was responsible for causing inhibition of the second heart.

He termed the unknown substance vagus-stoff.  Subsequent articles by Loewi provided additional evidence favoring the similarity of this substance to ACh, including its characteristic sensitivity to destruction by an esterase that Loewi had extracted from heart muscle. The substance was later identified as the neurotransmitter acetylcholine.

Loewi also proved both the SNS and the PNS response. Yet despite Loewi's research, and despite Dale's arguments in favor of the neurotransmitter theory, many continued to argue against it throughout the 1930s.  Although this work was vindicated in 1933 when Wilhelm Feldberg and Otto Krayer demonstrated "difinitively that the stimulation of the vagus nerve liberated ACh into the coronary vasculature of mammals." (2)

As a reward for their hard work, Dale and Loewi received the noble prize in 1936 "for their work on chemical transmission of nerve impulses."  (2) Despite all this research and improved wisdom of how drugs work, the next effective synthesized version of adrenaline was not available until 1949 when Isoproterenol was synthesized.  It ultimately would become the most popular asthma drug during the 1950s through the 1970s.

Further reading:
  1. 1901: Epinephrine (adrenaline) discovered
  2. 1833-1957: Research leads to asthma rescue medicine
  3. 1900-present: The evolution of rescue medicine
  4. How does respiratory medicine like epinephrine, albuterol, levalbuterol work? (The updated wisdom)
References:

  1. "Sympathetic Nervous System," sciencedaily.com,, accessed 3/7/13 
  2. Rubin, Ronald P., "A Brief History of Great Discoveries in Pharmacology: In Celebration of teh Centennial Anniversary of the Founding of the American Socieity of Pharmacology and Experimental Therapeutics," Pharmacological Reviews, December, 2007, vol. 59, no. 4, pages 289-359 (This article provides a good history of the discoveries of the sympathetic nervous system, the neuromuscular synapse, and how hormones such as adrenaline work)
  3. McFadden, E.R., "A Century of Asthma," American Journal of Respiratory Critical Care, August 1, 2004, volume 170, no. 3, pages 215-221
  4. Sneader, Walter, "Drug Discovery: A History," 2005, Wiley, Great Britain,  page 155-157. (Sneader provides a very thorough history of the discovery of hormone therapy in the later portion of the 19th century.)
  5. Sander, Mark, "Inhalation Therapy: An Historic Review," Primary Care Respiratory Journal, 2007,  16 (2), pages 71-81
  6. Valeri, Andrea, Carlo Bergamini, Rocco Bellantone, Celestino Pio Lombardi, editors, "Surgery of the Adrenal Gland," 2013, New York, London, Springer

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