In middle and high school you learn that nerve cells carry information as electrical impulses called action potentials, but there is a tiny space between cells called the synapse. Dale and Loewi showed that the signal does not jump across as pure electricity; instead, chemicals such as acetylcholine are released to excite the next cell. Loewi’s famous frog-heart experiment, in which fluid from one stimulated heart changed the beat of another heart, provided direct proof. Dale purified acetylcholine and studied its detailed effects in the autonomic nervous system. Their work revealed that neurons operate through a hybrid of electricity and chemistry, paving the way for drugs used in Parkinson’s and Alzheimer’s disease. It also became essential for understanding how nerve poisons and pesticides work. Today, every biology textbook explains neurotransmitters on the basis of their pioneering results.

In the early 20th century, physiologists debated whether nerve communication was electrical or chemical. In 1921, Loewi’s perfused frog-heart experiment demonstrated that fluid collected after vagus-nerve stimulation slowed the beating of a second heart, providing direct evidence for a soluble mediator. He temporarily called the substance “Vagusstoff,” which was soon identified as acetylcholine, a compound already isolated by Dale. Dale systematically studied acetylcholine’s pharmacology in the sympathetic and parasympathetic systems and distinguished nicotinic and muscarinic receptor actions by using plant alkaloids. The work contributed to what became known as “Dale’s principle,” the idea that a given neuron typically releases one primary transmitter at all its terminals. Their discoveries laid foundations for the synaptic vesicle model and the concept of quantal release, influencing physiology, pharmacology, neuroscience, and clinical medicine. Modern cholinesterase inhibitors, neuromuscular blockers, and anti-Alzheimer’s agents are direct descendants of their findings. The differentiation between chemical and electrical (gap-junction) synapses in today’s textbooks traces back to the conceptual framework they provided.

During the 1920s the debate over neural signaling intensified between proponents of the electrical and chemical hypotheses. Loewi designed a dual-atrial Ringer perfusion system; by transferring the perfusate within 15 s after vagus stimulation he reproduced the negative chronotropic effect in a second heart, quantitatively matching acetylcholine hydrolysis kinetics. Dale combined tissue extraction with in-vivo pharmacology to quantify acetylcholine at the μmol g⁻¹ level and pharmacologically separated nicotinic and muscarinic receptor subtypes. Although exceptions such as cotransmission were later found, Dale’s principle remains valuable for understanding neuronal differentiation and gene-expression programs. Their findings flowed directly into Katz and Fatt’s quantal release theory, the identification of synaptic SNARE proteins, and the discovery of G-protein-gated inwardly rectifying K⁺ channels, underpinning modern therapies that target cholinergic transmission.