Non-adrenergic non-cholinergic (NANC) transmission to smooth muscle: 35 years on

In 1963, two substances were thought to mediate all transmission between neurons, as well as between nerve and muscle in the peripheral nervous system, namely acetylcholine and noradrenaline. This paradigm primarily was due to the research of Dale, Loewi and von Euler in the first half of the century [Dale, 1937 (Transmission of nervous effects by acetylcholine, Harvey Lect. 32, pp. 229-245)]. However, in 1963, a series of experiments were carried out using recently introduced electrophysiological techniques, which showed unequivocally for the first time that the classical paradigm was not correct. Both inhibitory and excitatory junctions between nerves and smooth muscle cells were shown to exist in which transmission was mediated by non-adrenergic, non-cholinergic (NANC) transmitters. In the succeeding 35 years, identification of these NANC transmitters has been a major task of neuropharmacology, with nitric oxide, neuropeptides, and purines being isolated. This review presents an historical account of the developments this century of the classical paradigm, of how it was displaced, and of the progress made in identifying the neuromuscular transmitters of the autonomic nervous system.