Vagusstoff
Encyclopedia
Vagusstoff refers to the substance released by stimulation of the vagus nerve
which causes a reduction in the heart
rate. Discovered in 1921 by physiologist Otto Loewi
, vagusstoff was the first confirmation of chemical synaptic transmission
and the first neurotransmitter
ever discovered. It was later confirmed to be acetylcholine
, which was first identified by Sir Henry Hallett Dale
in 1914. Because of his pioneering experiments, in 1936 Loewi was awarded the Nobel Prize in Physiology or Medicine
, which he shared with Dale.
s and muscle
s was chemical or electrical by nature. Experiments by Luigi Galvani
in the 18th century had demonstrated that electrical stimulation of the frog sciatic nerve
resulted in twitching of the leg muscles, and from this he developed the concept of bioelectricity. This led to the idea that direct electrical contact between nerves and muscles mediated transmission of excitation. However, work by John Newport Langley had suggested that in the autonomic nervous system
communication in the ciliary ganglion
was chemical. Loewi's experiments, published in 1921 http://www.springerlink.com/media/hb5c1xjkyj5xwgb1va6q/contributions/x/0/1/3/x01314653605h385.pdf, finally settled the issue, proving that synaptic transmission was chemical.
Loewi performed a very simple yet elegant experiment. Using an isolated frog
heart he had previously found that stimulation of the vagus nerve resulted in a slowing of the heart rate
, while stimulation of the sympathetic nerve caused the heart rate to speed up (Figure 1). He reasoned that stimulation of either the vagus or sympathetic nerve would cause the nerve terminal to release a substance which would either slow or accelerate the heart rate. To prove this, he took a frog heart, which had been cannulated
in order to perfuse the fluid surrounding the heart, and electrically stimulated the vagus nerve until the heart rate slowed. He then collected the fluid surrounding the heart and added it to a second frog heart which had been stripped of its vagal and sympathetic nerves. By adding the fluid surrounding the first heart to the second heart, he caused the heart rate of the second heart to slow down. This proved that stimulation of the vagus nerve caused the release of a substance which acted upon the heart tissue and directly caused the heart rate to slow down. (Figure 2) This substance was called vagusstoff. Vagustoff was later confirmed to be acetylcholine
and was found to be the principal neurotransmitter in the parasympathetic nervous system
.
In an interesting aside, Loewi apparently had the idea for his experiment in a dream
. He wrote it down in the middle of the night but the next morning could not decipher his writing. He eventually had the same dream on another night, and decided to run to the laboratory to perform the experiment in the middle of the night. About this incident, Loewi writes:
While it remains unclear how much of Loewi's account is true, Loewi was fortunate in his choice of experimental preparation. In the species of frog used (Rana esculenta), the vagus contains both inhibitory and stimulatory fibers. In the winter, inhibitory fibers predominate, so Loewi was also fortunate to have performed his experiments in February or March. Additionally, acetylcholinesterase
activity (the enzyme that degrades acetylcholine) is low, particularly in an unheated laboratory, allowing the neurotransmitter to remain long enough to be collected and applied to a second heart. Thanks to this confluence of events, Loewi was able to describe the existence of vagusstoff and prove the existence of chemical synaptic transmission.
Vagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
which causes a reduction in the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
rate. Discovered in 1921 by physiologist Otto Loewi
Otto Loewi
Otto Loewi was a German born pharmacologist whose discovery of acetylcholine helped enhance medical therapy. The discovery earned for him the Nobel Prize in Physiology or Medicine in 1936 which he shared with Sir Henry Dale, whom he met in 1902 when spending some months in Ernest Starling's...
, vagusstoff was the first confirmation of chemical synaptic transmission
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
and the first neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
ever discovered. It was later confirmed to be acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, which was first identified by Sir Henry Hallett Dale
Henry Hallett Dale
Sir Henry Hallett Dale, OM, GBE, PRS was an English pharmacologist and physiologist. For his study of acetylcholine as agent in the chemical transmission of nerve impulses he shared the 1936 Nobel Prize in Physiology or Medicine with Otto Loewi.-Biography:Henry Hallett Dale was born in Islington,...
in 1914. Because of his pioneering experiments, in 1936 Loewi was awarded the Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
, which he shared with Dale.
The discovery of Vagusstoff
By the time Loewi began his experiments there was much discussion among scientists whether communication between nerveNerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s and muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
s was chemical or electrical by nature. Experiments by Luigi Galvani
Luigi Galvani
Luigi Aloisio Galvani was an Italian physician and physicist who lived and died in Bologna. In 1791, he discovered that the muscles of dead frogs legs twitched when struck by a spark...
in the 18th century had demonstrated that electrical stimulation of the frog sciatic nerve
Sciatic nerve
The sciatic nerve is a large nerve fiber in humans and other animals. It begins in the lower back and runs through the buttock and down the lower limb...
resulted in twitching of the leg muscles, and from this he developed the concept of bioelectricity. This led to the idea that direct electrical contact between nerves and muscles mediated transmission of excitation. However, work by John Newport Langley had suggested that in the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
communication in the ciliary ganglion
Ciliary ganglion
The ciliary ganglion is a parasympathetic ganglion located in the posterior orbit. It measures 1–2 millimeters in diameter and contains approximately 2,500 neurons. Preganglionic axons from the Edinger-Westphal nucleus travel along the oculomotor nerve and form synapses with these cells...
was chemical. Loewi's experiments, published in 1921 http://www.springerlink.com/media/hb5c1xjkyj5xwgb1va6q/contributions/x/0/1/3/x01314653605h385.pdf, finally settled the issue, proving that synaptic transmission was chemical.
Frog
Frogs are amphibians in the order Anura , formerly referred to as Salientia . Most frogs are characterized by a short body, webbed digits , protruding eyes and the absence of a tail...
heart he had previously found that stimulation of the vagus nerve resulted in a slowing of the heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
, while stimulation of the sympathetic nerve caused the heart rate to speed up (Figure 1). He reasoned that stimulation of either the vagus or sympathetic nerve would cause the nerve terminal to release a substance which would either slow or accelerate the heart rate. To prove this, he took a frog heart, which had been cannulated
Cannula
A cannula or canula is a tube that can be inserted into the body, often for the delivery or removal of fluid or for the gathering of data...
in order to perfuse the fluid surrounding the heart, and electrically stimulated the vagus nerve until the heart rate slowed. He then collected the fluid surrounding the heart and added it to a second frog heart which had been stripped of its vagal and sympathetic nerves. By adding the fluid surrounding the first heart to the second heart, he caused the heart rate of the second heart to slow down. This proved that stimulation of the vagus nerve caused the release of a substance which acted upon the heart tissue and directly caused the heart rate to slow down. (Figure 2) This substance was called vagusstoff. Vagustoff was later confirmed to be acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
and was found to be the principal neurotransmitter in the parasympathetic nervous system
Parasympathetic nervous system
The parasympathetic nervous system is one of the two main divisions of the autonomic nervous system . The ANS is responsible for regulation of internal organs and glands, which occurs unconsciously...
.
In an interesting aside, Loewi apparently had the idea for his experiment in a dream
Dream
Dreams are successions of images, ideas, emotions, and sensations that occur involuntarily in the mind during certain stages of sleep. The content and purpose of dreams are not definitively understood, though they have been a topic of scientific speculation, philosophical intrigue and religious...
. He wrote it down in the middle of the night but the next morning could not decipher his writing. He eventually had the same dream on another night, and decided to run to the laboratory to perform the experiment in the middle of the night. About this incident, Loewi writes:
- On mature consideration, in the cold light of the morning, I would not have done it. After all, it was an unlikely enough assumption that the vagus should secrete an inhibitory substance; it was still more unlikely that a chemical substance that was supposed to be effective at very close range between nerve terminal and muscle be secreted in such large amounts that it would spill over and, after being diluted by the perfusion fluid, still be able to inhibit another heart. (Loewi 1921)
While it remains unclear how much of Loewi's account is true, Loewi was fortunate in his choice of experimental preparation. In the species of frog used (Rana esculenta), the vagus contains both inhibitory and stimulatory fibers. In the winter, inhibitory fibers predominate, so Loewi was also fortunate to have performed his experiments in February or March. Additionally, acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
activity (the enzyme that degrades acetylcholine) is low, particularly in an unheated laboratory, allowing the neurotransmitter to remain long enough to be collected and applied to a second heart. Thanks to this confluence of events, Loewi was able to describe the existence of vagusstoff and prove the existence of chemical synaptic transmission.
Sources
- O. Loewi (1921) "Über humorale Übertragbarkeit der Herznervenwirkung. I." Pflügers Archiv, 189, pp. 239-242
- M.R. Bennett (2000) "The concept of transmitter receptors: 100 years on", Neuropharmacology, 39(4):523-46.
- J.G. Nicholls, A.R. Martin, B.G. Wallace and P.A. Fuchs. "From Neuron to Brain". 4th ed. Sinauer Associates, Sunderland, MA. ISBN 0-87893-439-1