A new chapter was opened when Max Lewandowsky in 1899 in Berlin observed that adrenal extracts acted on the smooth muscle of the eye and orbit of cats — such as the iris dilator muscle and nictitating membrane — in the same way as sympathetic nerve stimulation. The correspondence was extended by John Newport Langley and, under his supervision, Thomas Renton Elliott in Cambridge. In four papers in volume 31, 1904, of the Journal of Physiology Elliott described the similarities organ by organ. His hypothesis stands in the abstract of a presentation to the Physiological Society of May 21, 1904, a little over ten years after Oliver and Schafer's presentation: ″Adrenalin does not excite sympathetic ganglia when applied to them directly, as does nicotine. Its effective action is localized at the periphery. I find that even after complete denervation, whether of three days’ or ten months’ duration, the plain muscle of the dilatator pupillae will respond to adrenalin, and that with greater rapidity and longer persistence than does the iris whose nervous relations are uninjured. Therefore, it cannot be than adrenalin excites any structure derived from, and dependent for its persistence on, the peripheral neurone. ... The point at which the stimulus of the chemical excitant is received, and transformed into what may cause the change of tension of the muscle fiber, is perhaps a mechanism developed out of the muscle cell in response to its union with the synapsing sympathetic fiber, the function of which is to receive and transform the nervous impulse. "Adrenalin" might then be the chemical stimulant liberated on each occasion when the impulse arrives at the periphery.″ The abstract is the ″birth certificate″ of chemical neurotransmission. Elliott was never so explicit again. It seems he was discouraged by the lack of a favorable response from his seniors, Langley in particular, and a few years later he left physiological research.
The breakthrough for chemical neurotransmission came when, in 1921, Otto Loewi in Graz demonstrated the ″humorale Übertragbarkeit der Herznervenwirkung″ in amphibians. Vagusstoff transmitted inhibition from the vagus nerves, and Acceleransstoff transmitted stimulation from the sympathetic nerves to the heart. Loewi took some years to commit himself with respect to the nature of the Stoffe, but in 1926 he was sure that Vagusstoff was acetylcholine, writing in 1936 ″I no longer hesitate to identify the Sympathicusstoff with adrenaline.″
He was correct in the latter statement. In most amphibian organs including the heart, the concentration of adrenaline far exceeds that of noradrenaline, and adrenaline is indeed the main transmitter. In mammals, however, difficulties arose. In a comprehensive structure-activity study of adrenaline-like compounds, Dale and the chemist George Barger in 1910 found that Elliotts hypothesis assumed a stricter parallelism between the effects of sympathetic nerve impulses and adrenaline than actually existed. For example, sympathetic impulses shared with adrenaline contractile effects in the trigone but not relaxant effects in the fundus of the cats urinary bladder. In this respect, ″amino-ethanol-catechol″ – noradrenaline – mimicked sympathetic nerves more closely than adrenaline did. The Harvard Medical School physiologist Walter Bradford Cannon, who had popularized the idea of a sympatho-adrenal system preparing the body for fight and flight, and his colleague Arturo Rosenblueth developed an elaborate but ″queer″ theory of two sympathins, sympathin E (excitatory) and sympathin I (inhibitory). The Belgian pharmacologist Zénon Bacq as well as Canadian and US-American pharmacologists between 1934 and 1938 suggested that noradrenaline might be the – or at least one – postganglionic sympathetic transmitter. However, nothing definite was brought to light till after the war. In the meantime, Dale created a terminology that has since imprinted the thinking of neuroscientists: nerve cells should be named after their transmitter, i.e. cholinergic if the transmitter was ″a substance like acetylcholine", and adrenergic if it was ″some substance like adrenaline″.
In 1936, the year when Loewi accepted adrenaline as the (amphibian) sympathetic transmitter, Dale and Loewi received the Nobel Prize in Physiology or Medicine ″for their discoveries relating to chemical transmission of nerve impulses″.