Evidence for ATP and noradrenaline as cotransmitters in sympathetic nerves

Sympathetically innervated smooth muscles, including those in some arteries, arterioles, cat nictitating membrane and vas deferens, have α1-adrenoceptors which respond to exogenously applied noradrenaline (NA) by producing contractions which can be abolished by α1-adrenoceptor antagonists such as prazosin. Stimulation of the sympathetic nerves innervating these muscles causes release of NA and a contractile response. However, this contraction is (at least partly) resistant to specific α1-adrenoceptor antagonists. This apparent contradiction could be explained by a variety of ad hoc explanations (such as high transmitter concentrations within the nerve-muscle junction, or prejunctional enhancement of transmitter release by the antagonist due to prejunctional α2-adrenoceptor blockade etc.) but recently two hypotheses have been advanced which may have more fundamental implications for sympathetic neurotransmission. First, Hirst and Neild and their colleagues suggested that the electrical and mechanical responses of some smooth muscles were resistant to α-adrenoceptor antagonists because neuronally released NA was acting not only on α-adrenoceptors but also on a new class of adrenoceptors which they designated γ-receptors, located near the nerve-muscle junction. The crucial experiments in support of this hypothesis were originally performed on the arterioles of the guinea-pig submucosa [1], but the idea has been extended to include many other sympathetically innervated smooth muscles [2], including guinea-pig vas deferens, which was also the smooth muscle preparation in which the experimental evidence for an alternative hypothesis was obtained by Fedan et al. [3]. They proposed that the α-blocker-resistant portion of the contractile response to sympathetic nerve stimulation was mediated by ATP, acting as a cotransmitter with NA. Full details of the early development of the concept of cotransmission in sympathetic nerves have been reviewed previously [4, 6, 7]. The experimental evidence relating to the co-transmission hypothesis is outlined below, drawing mainly on results obtained in guinea-pig vas deferens, where most of the more recent experiments have been performed.