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New Concepts of Transmitter Action

Until recently, nervous control of the vasculature was considered predominantly in terms of classic transmitters: norepinephrine and acetylcholine. For many years, they were the only transmitters recognized in perivascular nerves.

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Beginning in the early 1960s, various other compounds, including monoamines, purines, amino acids, and polypeptides, were identified that fulfilled the criteria of functional neurotransmitters.[1] [2] As reviewed by Burnstock,[3] nonadrenergic, noncholinergic components are part of the ANS. Other transmitter candidates demonstrated in perivascular nerves using histochemical and immunohistochemical techniques include adenosine 5'-triphosphate (ATP), vasoactive intestinal polypeptide (VIP), substance P, 5-hydroxytryptamine (5-HT), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP). Immunocytochemical studies show that more than one transmitter or putative transmitter may be colocalized in the same nerve. The most common combinations of transmitters in perivascular nerves are norepinephrine, ATP, and NPY in sympathetic nerves; acetylcholine and VIP in parasympathetic nerves; and substance P, CGRP, and ATP in sensory-motor nerves. Many of these putative transmitters act through cotransmission, which is the synthesis, storage, and release of more than one transmitter by a nerve. [4] Initially, the multiplicity of transmitters released in various combinations appeared random and bewildering, but a pattern is emerging that clarifies the situation. Autonomic nerves exhibit chemical coding—individual neurons serving a specific physiologic function contain distinct combinations of transmitter substances.[5]


Figure 16-2 The diagram shows that adenosine triphosphate (ATP) and norepinephrine (NE) are released as cotransmitters from the sympathetic nerves supplying the vas deferens and some blood vessels. ATP acts on P2 -purinoceptors on the smooth muscles to initiate excitatory junction potentials, action potentials, and a fast initial contraction involving electromechanical coupling through voltage-dependent calcium (Ca2+ ) channels. NE acts on α1 -adrenoceptors to produce the second, slower phase of the contraction by pharmacomechanical (or at least spike-independent) coupling through receptor-operated Ca2+ channels. Prejunctional α2 -adrenoceptors and P1 -purinoceptors can reduce transmitter release when activated by NE and adenosine (AD), respectively (i.e., prejunctional neuromodulation), whereas NE and ATP enhance each other's actions (i.e., postjunctional neuromodulation). (Adapted from Burnstock G: Local mechanisms of blood flow control by perivascular nerves and endothelium. J Hypertens Suppl 8:S95, 1990.)

The concepts of cotransmission and neuromodulation have become accepted mechanisms in autonomic nervous control. To establish that transmitters coexisting in the same nerves act as cotransmitters, it is necessary to demonstrate that, on release, each substance acts postjunctionally on its own specific receptor to produce a response.

For many perivascular sympathetic nerves, there is evidence that norepinephrine and ATP act as cotransmitters and are released from the same nerves but act on α1 -adrenoceptors and P2 -purinoceptors, respectively, to produce vasoconstriction[6] [7] ( Fig. 16-2 ). ATP, once thought to act only as an electrical buffer for the charged norepinephrine, is believed to mediate contraction through P2x -receptors by voltage-dependent calcium channels.[8] The fast component of contraction appears to be mediated by these purinoceptors, whereas norepinephrine sustains contraction of muscle by acting on the α1 -adrenoreceptor through receptor-operated calcium channels. Specific drugs have been designed to interact with this purinergic component.[9]

Neuromodulators modify the process of neurotransmission. They may be circulating neurohormones, local agents, or neurotransmitter substances released from the same nerves or from others nearby. Neuromodulation can occur prejunctionally by decreasing or increasing the amount of transmitter released during transmission or

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postjunctionally by altering the extent or time course of neurotransmitter effect. In all known examples in which prejunctional and postjunctional neuromodulation occurs, these substances act in concert to attenuate or to augment effective transmission. The rationale for such effects may reflect the variable geometry of the autonomic neuroeffector junction.[10] [11] Unlike the neuromuscular junction, the autonomic neuroeffector junction exists in a dynamic state and manifests only modest postjunctional specialization. Biogenic amines often must traverse wide distances. Given the short half-lives of these chemicals, neuromodulation provides a biologic mechanism for augmentation and prolongation of their action.[12]

NPY is also colocalized with norepinephrine and ATP. However, in some vessels, NPY has little or no direct action; instead, NPY acts as a neuromodulator prejunctionally to inhibit the release of norepinephrine from the nerve or postjunctionally to enhance the action of norepinephrine ( Fig. 16-3A ).[13] [14] In other vessels, notably those of the spleen, skeletal muscle, and cerebral and


Figure 16-3 Schematic representation of different interactions that occur between neuropeptide Y (NPY) and adenosine triphosphate (ATP), and norepinephrine (NE) released from single sympathetic nerve varicosities. A, Diagram shows what occurs in the vas deferens and many blood vessels, where NE and ATP, probably released from small granular vesicles, act synergistically to contract (+) the smooth muscle through α1 -adrenoceptors and P2 -purinoceptors, respectively. B and C, Sympathetic neurotransmission in the heart and brain (B) and spleen (C). (From Lincoln J, Burnstock G: Neural-endothelial interactions in control of local blood flow. In Warren J [ed]: The Endothelium: An Introduction to Current Research. New York, Wiley-Liss, 1990, p 21.)

coronary vasculature, NPY has direct vasoconstrictor actions. In the heart and brain, local intrinsic (nonsympathetic) neurons use NPY as the principal transmitter (see Fig. 16-3B ). In the spleen, NPY appears to act as a genuine cotransmitter with norepinephrine in perivascular sympathetic nerves (see Fig. 16-3C ). [15] The frequency of stimulation determines which vesicles are mobilized to release their transmitters.

A classic transmitter such as acetylcholine coexists with VIP in the parasympathetic nerves of many organs, but in this instance, the two transmitters are stored in separate vesicles. They can be released differentially at different stimulation frequencies, depending on where they are located.[16] [17] For example, in the salivary gland, they can act independently on acinar cells and glandular blood vessels ( Fig. 16-4 ).[7] Cooperation is achieved by the selective release of acetylcholine at low frequencies and of VIP at high frequencies of stimulation. Elements of prejunctional and postjunctional modulation have also been described. It is becoming increasingly apparent that in many biologic states, including pregnancy,[18]

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Figure 16-4 A classic transmitter, acetylcholine (ACh), coexists with vasoactive intestinal polypeptide (VIP) in parasympathetic nerves supplying the cat salivary gland. ACh and VIP are stored in separate vesicles; they can be released differentially at different stimulation frequencies to act on acinar cells and glandular blood vessels. Cooperation is achieved by the selected release of ACh at low impulse frequencies and of VIP at high frequencies. Prejunctional and postjunctional modulation is indicated. (From Burnstock G: Local mechanisms of blood flow control by perivascular nerves and endothelium. J Hypertens Suppl 8:S95, 1990.)

hypertension, and aging, the relationships among cotransmitters may be an important determinant of a compensatory response, allowing finer control of important physiologic function.

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