Loewi's experimental discovery of chemical neurotransmission.

German physiologist Otto Loewi was interested in how neurons communicate with muscle. He already knew that the electrical stimulation of a nerve in a frog's leg would result in muscle contraction, so it appeared that neurons communicate with the muscle by electrical signals. In the early 1920s, he turned his studies to the heart. If he removed a frog's heart and put it in a bath containing saline, it continued to beat for several hours. All vertebrate hearts receive both stimulatory and inhibitory nerve impulses that regulate the rhythm and intensity of the heartbeat. When dissected from an animal, these nerves remain attached to the heart and their function can be studied in a bath solution.

When Loewi electrically stimulated a certain nerve attached to the frog's heart, the rate at which the heart contracted increased. However, if he stimulated a different nerve, known as the vagus nerve, the heart rate decreased. Loewi wondered how electrical activity in different neurons could have opposite effects. He hypothesized that a stimulated neuron released a chemical substance that could influence muscles and other neurons in different ways, but he did not know how to test the hypothesis. As he described later, the idea for the definitive experiment came to him in the middle of the night: “The night before the Easter Sunday of that year I awoke, turned on the light, and jotted down a few notes on a tiny slip of paper. Then I fell asleep again. It occurred to me at six o'clock in the morning that during the night I had written down something most important, but I was unable to decipher the scrawl. The next night, at three o'clock, the idea returned. … I got up immediately, went to the laboratory, and performed a simple experiment on a frog heart according to the nocturnal design.”

As shown in the figure above, Loewi placed two frog hearts in separate, but connected, chambers containing saline. He used an electrode to stimulate the vagus nerve that was still attached to the first heart and recorded the heart rate. As he expected from an earlier experiment, the heart rate slowed. Within a few minutes, the heart rate of the second heart also slowed even though he had not stimulated the nerve to that heart at all. He concluded that a chemical substance was released from the nerve of the first heart into the surrounding fluid and diffused into the second chamber, where it exerted its effects on the second heart.

Loewi initially named this substance Vagusstoff (vagus substance) after the vagus nerve he stimulated, but it was later renamed acetylcholine when its chemical nature (acetic acid bonded to choline) was determined. Acetylcholine was the first neurotransmitter discovered, which was a major achievement in neuroscience. Loewi's research opened the door for what we now know about chemical transmission at synapses, and the enormous pharmaceutical industry, which builds on this knowledge to treat neurological disorders.