Minireview. Presynaptic receptors and alterations in norepinephrine release in spontaneously hypertensive rats

The ability of blood vessels to constrict to a given stimulus is significantly increased in spontaneously hypertensive rats (SHR). Such an increase in the vasoconstrictor responsiveness contributes to the elevated peripheral vascular resistance noted in SHR. The present review discusses evidence in support of the concept that an increased release of norepinephrine during sympathetic nerve stimulation may contribute to the increase in vasoconstrictor responsiveness and, subsequently, to an increase in vascular resistance in the SHR. Several studies suggest that the exocytotic release of norepinephrine from sympathetic nerves may be altered by endogenously occurring neurohumoral substances which produce their effects by interacting with presynaptic receptors located on postganglionic sympathetic nerves. Therefore, it is postulated that alterations in presynaptic regulation of norepinephrine release, resulting from changes in the functioning of one or more of these presynaptic receptors, may lead to a greater release of norepinephrine in the SHR. This review summarizes the results of studies evaluating presynaptic receptor mechanisms and norepinephrine release in the SHR. These studies suggest that norepinephrine release during sympathetic nerve stimulation is greater in the SHR and that alterations in some of the presynaptic receptor mechanisms may be responsible for this phenomenon.     

Analysis of presynaptic inhibitory actions of various dopamine analogs on sympathetic neurotransmission in mongrel dogs.

A study was designed to investigate the effects of dopamine, α-methyldopamine and epinine on sympathetic neurotransmission to the myocardium by studying the chronotropic responses to cardioaccelerator nerve stimulation in pentobarbital anesthetized, desipramine treated dogs. During infusions of either one of the three amines, responses to cardiac nerve stimulation were significantly impaired at all the frequencies. Dopamine and epinine induced attenuation of chronotropic responses to cardiac nerve stimulation were completely prevented by prior treatment with haloperidol, while phentolamine caused only partial restoration of nerve stimulation responses. On the other hand, the impairment of nerve stimulation responses caused by α-methyldopamine were completely restored to control level by phentolamine treatment, while haloperidol caused only partial restoration. Evaluation of the effects of these agents on blood pressure of pentobarbital anesthetized dogs revealed that dopamine and epinine caused a depressor response following appropriate pretreatment, part of which was mediated via the action of these agents on postsynaptic dopaminergic receptors. However, α-methyldopamine failed to lower blood pressure in these dogs. These results support the concept for the existence of two presynaptic receptor mechanisms on the sympathetic nerve terminals and demonstrate that the inhibition of responses to nerve stimulation caused by dopamine and epinine was mediated via their action on presynaptic dopaminergic receptors while α-methyldopamine produced impairment of nervous transmission by acting on presynaptic alpha adrenergic receptors. Furthermore, although presynaptic alpha adrenergic receptors do play a functional role in modulating sympathetic transmission during nerve stimulation, presynaptic dopaminergic receptors do not seem to have a physiological role in this process.     

Receptor-Mediated Interaction Between the Sympathetic Nervous System and Immune System in Inflammation

The sympathetic nervous system plays a central role in establishing communication between the central nervous system and the immune system during inflammation. Inflammation activates the sympathetic nervous system, which causes release of the transmitters of the sympathetic nerv-ous system in the periphery. The transmitters of the sympathetic nervous system are the cate-cholamines noradrenaline and adrenaline and the purines ATP, adenosine, and inosine. Once these transmitters are released, they stimulate both presynaptic receptors on nerve terminals and post-synaptic receptors on immune cells. The receptors that are sensitive to catecholamines are termed adrenoceptors, whereas the receptors that bind purines are called purinoceptors. Stimulation of the presynaptic receptors exerts an autoregulatory effect on the release of transmitters. Ligation of the postsynaptic receptors on inflammatory cells modulates the inflammatory ac-tivities of these cells. The present review summarizes some of the most important aspects of the current state of knowledge about the interactions between the sympathetic nervous system and the immune system during inflammation with a special emphasis on the role of adreno and purinoceptors.     

Commande nerveuse peripherique de l’erection

Local mechanisms causing penile erection and detumescence result from variation in tone of vascular and trabecular smooth muscles and in a lesser part of striated muscles around the crura penis. All these events are neurally mediated. We reviewed human and animal data concerning the functional peripheral neuroanatorny of erection. General organization of peripheral nervous system is recalled. Somatic efferents of the pudendal nerve, originating in the sacral spinal cord, innervate the striated musculature of the perineum. Somatic afferents of the penis are conveyed by the dorsal penile nerve, a branch of the pudendal nerve. Afferent terminations project into the spinal cord, their role is discussed. Parasympathetic pathways are involved in the reflexogenic erections. Sympathetic pathways destinated to the erectile structures are more complex. They are issued from thoracolumbar spinal cord and travel through the hypogastric nerve or the lumbosacral sympathetic chain. Sympathetic fibers originating in the sacral sympathetic chain are present in both pelvic and pudendal nerves. Inhibitory role on the erection of the sympathetic nervous system is well-known, it could be also responsible for psychogenic erections. Parasympathetic and sympathetic fibees are mixed in the pelvic plexus and the cavernous nerves which are described. Relations between the four sets of peripheral nerves (somatic efferents, penile afferents, thoracolumbar sympathetic sacral parasympathetic and sympathetic) are discussed.     

Vascular adrenergic interactions during hemorrhagic shock

The objective of this paper is to review the sequence of vascular events that follows severe hemorrhage. The initial cardiovascular imbalance is a fall in the volume/vascular capacity relationship that leads to reductions in cardiac output and mean arterial pressure (MAP). Peripheral sensors detect the fall in MAP and changes in blood chemistry that cause withdrawal of the normal inhibitory tone from the cardiovascular control centers in the central nervous system. The resulting increased sympathetic activity initiates a series of events that include stimulation of peripheral adrenergic nerves and the adrenal medulla. The magnitude of the compensatory vasoconstriction that follows is the net result of the interaction of the epinephrine (E) from the adrenal medulla and norepinephrine (NE) from the peripheral nerves on the peripheral vascular adrenoreceptors as well as other nonadrenergic mechanisms not discussed here (i.e., angiotensin endogenous opiates). By using pharmacological blocking agents, these adrenoreceptors have been subclassified as: innervated postsynaptic alpha 1; presynaptic alpha 2 (Ps alpha 2); and extrasynaptic alpha 2 (Es alpha 2) adrenoreceptors. The action of E and NE on the alpha 1 and Es alpha 2 receptors initiates the compensatory vasoconstriction, whereas action of these catecholamines on the Ps alpha 2 located on the presynaptic membrane inhibits further release of NE from peripheral nerve terminals, thereby reducing the effect of the innervated alpha 1 receptors. This autoinhibition together with a similar action by prostaglandin E on NE release is thought to be, at least in part, responsible for the vascular decompensation known to occur in the skeletal muscle after hemorrhage. Thus, one of the factors determining survival after hemorrhage may be related to the relative dominance of alpha 1 and Es alpha 2 receptors during the initial compensatory response.     

The distribution of sympathetic nerve fibres in the AV node and AV bundle of the bovine heart

The sympathetic nervous system has important effects on the properties of the heart, including the conduction of the impulse. However, it is not known how this nervous system is distributed in the atrioventricular (AV) bundle, which together with the AV node constitutes the only conduction pathway between the atria and ventricles in normal hearts. Therefore, in the present study the adrenergic innervation in the bovine AV node/AV bundle was examined by use of the glyoxylic acid induced method for histofluorescence demonstration of catecholamines. Acetylcholinesterase (AChE) histochemistry was also used. It was found that the AChE-positive nerve fascicles in these regions partly contain sympathetic nerve fibres, that sympathetic nerve fibres occur in the proximity of some of the ganglionic cells that occur outside the AV node/AV bundle, that the arteries supplying AV bundle tissue as well as AV nodal tissue have perivascular plexuses of sympathetic nerve fibres, and that there is a substantial number of sympathetic nerve fibres outside Purkinje fibre bundle surfaces. The observations give new insight into the question of the distribution of the sympathetic nerves in the AV bundle in relation to the distribution of these nerves in the AV node. Possible functional implications of the observations are discussed.     

Sympathetic neurons mediate developmental change in cardiac sodium channel gating through long-term neurotransmitter action.

Innervation of nerve and muscle cells during development is often accompanied by changes in the expression and function of ion channels in the postsynaptic cell. However, the signaling pathways whereby the presynaptic nerve influences the properties of the postsynaptic cell are less well understood. Indirect evidence suggests that cardiac voltage-gated Na+ channels undergo important changes during development. Here, we compare directly single voltage-gated Na+ channel currents from neonatal and adult rat ventricular myocytes and report a negative shift in the voltage dependence of channel gating during development, leading to a significant speeding of channel activation and inactivation at a fixed membrane potential. These developmental changes can be mimicked in vitro by innervation of neonatal myocytes with sympathetic neurons. The effect of sympathetic neurons is blocked by the beta-adrenergic receptor antagonist propranolol and is mimicked by prolonged coculture of neonatal myocytes with a membrane-permeable cAMP analog. Thus presynaptic neurons can control the developmental phenotype of ion channels in a postsynaptic cell through a classic receptor-mediated neurotransmitter action that involves a defined second messenger pathway.     

The Niemann-Pick C1 protein in recycling endosomes of presynaptic nerve terminals

Niemann-Pick type C (NPC) disease is a fatal, neurodegenerative disorder caused in 95% of cases by loss of function of NPC1, a ubiquitous endosomal transmembrane protein. A biochemical hallmark of NPC deficiency is cholesterol accumulation in the endocytic pathway. Although cholesterol trafficking defects are observed in all cell types, neurons are the most vulnerable to NPC1 deficiency, suggesting a specialized function for NPC1 in neurons. We investigated the subcellular localization of NPC1 in neurons to gain insight into the mechanism of action of NPC1 in neuronal metabolism. We show that NPC1 is abundant in axons of sympathetic neurons and is present in recycling endosomes in presynaptic nerve terminals. NPC1 deficiency causes morphological and biochemical changes in the presynaptic nerve terminal. Synaptic vesicles from Npc1(-/-) mice have normal cholesterol content but altered protein composition. We propose that NPC1 plays a previously unrecognized role in the presynaptic nerve terminal and that NPC1 deficiency at this site might contribute to the progressive neurological impairment in NPC disease.     

Adenosine modulation of vasoconstrictor responses to stimulation of sympathetic nerves and norepinephrine infusion in the superior mesenteric artery of the cat

Vasoconstriction induced by sympathetic nerve stimulation and by norepinephrine infusion in the superior mesenteric artery of cats anesthetized with pentobarbital was inhibited by adenosine infusions in a dose-related way. The responses to nerve stimulation were not inhibited to a greater extent than the responses to norepinephrine, thus suggesting no presynaptic modulation of sympathetic nerves supplying the resistance vessels of the feline intestinal vascular bed. Blockade of adenosine receptors using 8-phenyltheophylline did not alter the degree of constriction induced by nerve stimulation or norepinephrine infusion, indicating that in the fasted cat, endogenous adenosine co-released or released subsequent to constriction does not affect the peak vasoconstriction reached. Isoproterenol caused similar degrees of vasodilation as adenosine but did not show significant antagonism of the pooled responses to nerve stimulation or norepinephrine infusion; there was no tendency for the degree of dilation induced by isoproterenol to correlate with the inhibition of constrictor responses. Thus, the effect of adenosine on nerve- and norepinephrine-induced constriction is not secondary to nonspecific vasodilation.     

Nerve growth factor collaborates with myocyte-derived factors to promote development of presynaptic sites in cultured sympathetic neurons

Nerve growth factor (NGF) acutely modulates synaptic transmission between sympathetic neurons and their cardiac myocyte targets. NGF also has developmental effects in establishing the level of synaptic transmission between sympathetic neurons and myocytes in culture, although little is known about the mechanisms by which NGF influences this synaptic connectivity. Here we report that NGF acts in conjunction with factors produced by cardiac myocytes to promote neuronal contact with the target and the extension of synaptic vesicle-containing growth cones. In conjunction with previously published results showing that NGF has long-term effects on synaptic transmission between sympathetic neurons and myocytes, this work suggests that NGF acts to promote sympathetic neurotransmission by increasing the number of sympathetic fibers establishing target contact. Further, we found that developmental changes in cardiac myocytes led to an increase in the density of synaptic vesicle-containing variocosities along sympathetic fibers, a process regulated by NGF. Thus, as myocytes mature they produce factors that promote the formation of sympathetic presynaptic structures. These results argue that multiple target interactions regulate the extent of synapse formation between sympathetic neurons and cardiac cells and suggest that NGF promotes presynaptic development by increasing neuronal contact with myocyte-derived cell surface or matrix-associated factors.     

Regulation of Vesicle Traffic and Neurotransmitter Release in Isolated Nerve Terminals

In this overview current insights in the regulation of presynaptic transmitter release, mainly acquired in studies using isolated CNS nerve terminals are highlighted. The following aspects are described. (i) The usefulness of pinched-off nerve terminals, so-called synaptosomes, for biochemical and ultrastructural studies of presynaptic stimulus-secretion coupling. (ii) The regulation of neurotransmitter release by multiple Ca²⁺ channels, with special emphasis on the specificity of different classes of these channels with respect to the release of distinct types of neurotransmitters, that are often co-localized, such as amino acids and neuropeptides. (iii) Possible molecular mechanisms involved in targeting synaptic vesicle (SV) traffic toward the active zone. (iv) The role of presynaptic receptors in regulating transmitter release, with special emphasis on different glutamate subtype receptors. Isolated nerve terminals are of great value as model system in order to obtain a better understanding of the regulation of the release of distinct classes of neurotransmitters in tiny CNS nerve endings.     

Turning off neurotransmitters

The historic discovery that the catecholamine neurotransmitters of the sympathetic nervous system, norepinephrine and epinephrine, are inactivated through their reuptake by presynaptic nerve terminals provided new insights into neurotransmitter action and paved the way for the development of modern antidepressant drugs.     

THE EFFECT OF DEPRIVATION OF GLUCOSE ON THE ULTRASTRUCTURE AND FUNCTION OF THE SUPERIOR CERVICAL GANGLION OF THE RAT IN VITRO

The superior cervical sympathetic ganglion of the rat kept in vitro in a bicarbonate-buffered Krebs' solution retains its capacity for synaptic transmission and axonal conduction during more than 36 hr. After glucose withdrawal, synaptic transmission is lost in 2½ hr and this loss is irreversible; on the other hand, axonal conduction can still be measured on the postganglionic nerve for more than 24 hr after glucose deprivation. Electrophysiological measurements as well as electron microscope studies revealed specific changes at the level of the presynaptic terminal processes, while the ganglion cells and the satellite cells remained relatively unaltered. The presynaptic lesion due to lack of glucose can be prevented by keeping the preparation in vitro at 6°C. This strongly suggests that this lesion results from a major disturbance of the metabolism of the presynaptic fibers.     

Inhibition of parasympathetic axonal sprouting in the cat submandibular gland by sympathetic axons

Summary The sprouting of parasympathetic axons into the submandibular sympathetic nerve trunk following sympathetic denervation has been investigated. It was found that a permanent sympathetic denervation was necessary in order for the sprouting to develop and be maintained: if reinnervation by adrenergic nerves was delayed, the sprouting developed but was reduced at longer survival times when the original innervation was reestablished. The evidence for suppression of the cholinergic sprouting by the adrenergic axons is discussed, as is the evidence that these sprouts arise from the submandibular gland.     

The origin of sympathetic outflow in heart failure: the roles of angiotensin II and nitric oxide

The regulation of sympathetic nerve activity in chronic heart failure (CHF) has been an area of renewed investigation. Understanding the central mechanisms that are responsible for sympatho-excitation in this disease state may help in reducing the deleterious effects of chronic sympatho-excitation. This review will summarize our understanding of abnormal reflex control of the circulation in CHF. The roles of the arterial baroreflex, the chemoreflex, the cardiac sympathetic afferent reflex and the cardiopulmonary reflex are discussed. New experimental techniques that allow genetic manipulation of substances such as nitric oxide synthase in discrete areas of the brain aid in clarifying the role of NO in the modulation of sympathetic tone in the CHF state. Lastly, clinical implications of this work are discussed.     

Presynaptic beta(2)-adrenoceptors mediate nicotine-induced NOergic neurogenic dilation in porcine basilar arteries

We previously reported that nicotine-induced nitric oxide (NO)-mediated cerebral neurogenic vasodilation was dependent on intact sympathetic innervation. We hypothesized that nicotine acted on sympathetic nerve terminals to release norepinephrine (NE), which then acted on adrenoceptors located on the neighboring nitric oxidergic (NOergic) nerve terminals to release NO, resulting in vasodilation. The adrenoceptor subtype in mediating nicotine-induced vasodilation in isolated porcine basilar arterial rings denuded of endothelium was therefore examined pharmacologically and immunohistochemically. Results from using an in vitro tissue bath technique indicated that propranolol and preferential beta(2)-adrenoceptor antagonists (ICI-118,551 and butoxamine), in a concentration-dependent manner, blocked the relaxation induced by nicotine (100 microM) without affecting the relaxation elicited by transmural nerve stimulation (TNS, 8 Hz). In contrast, preferential beta(1)-adrenoceptor antagonists (atenolol and CGP-20712A) did not affect either nicotine- or TNS-induced relaxation. Results of double-labeling studies indicated that beta(2)-adrenoceptor immunoreactivities and NADPH diaphorase reactivities were colocalized in the same nerve fibers in basilar and middle cerebral arteries. These findings suggest that NE, which is released from sympathetic nerves upon application of nicotine, acts on presynaptic beta(2)-adrenoceptors located on the NOergic nerve terminals to release NO, resulting in vasodilation. In addition, nicotine-induced relaxation was enhanced by yohimbine, an alpha(2)-adrenoceptor antagonist, which, however, did not affect the relaxation elicited by TNS. Prazosin, an alpha(1)-adrenoceptor antagonist, on the other hand, did not have any effect on relaxation induced by either nicotine or TNS. The predominant facilitatory effect of beta(2)-adrenoceptors in releasing NO may be compromised by presynaptic alpha(2)-adrenoceptors.     

Specific Neurochemical Derangements of Brain Projecting Neurons in Apolipoprotein E-Deficient Mice

Abstract: Apolipoprotein E (apoE)-deficient mice provide a useful system for studying the role of apoE in neuronal maintenance and repair. Previous studies revealed specific memory impairments in these mice that are associated with presynaptic derangements in projecting forebrain cholinergic neurons. In the present study we examined whether dopaminergic, noradrenergic, and serotonergic projecting pathways of apoE-deficient mice are also affected and investigated the mechanisms that render them susceptible. The densities of nerve terminals of forebrain cholinergic projections were monitored histochemically by measurements of acetylcholinesterase activity, whereas those of the dopaminergic nigrostriatal pathway, the noradrenergic locus coeruleus cortical projection, and the raphe-cortical serotonergic tract were measured autoradiographically using radioligands that bind specifically to the respective presynaptic transporters of these neuronal tracts. The results obtained revealed that synaptic densities of cholinergic, noradrenergic, and serotonergic projections in specific brain regions of apoE-deficient mice are markedly lower than those of controls. Furthermore, the extent of presynaptic derangement within each of these tracts was found to be more pronounced the further away the nerve terminal is from its cell body. In contrast, the nerve terminal density of the dopaminergic neurons that project from the substantia nigra to the striatum was unaffected and was similar to that of the controls. The rank order of these presynaptic derangements at comparable distances from the respective cell bodies was found to be septohippocampal cholinergic > nucleus basalis cholinergic > locus coeruleus adrenergic > raphe serotonergic ? nigrostriatal dopaminergic, which interestingly is similar to that observed in Alzheimer's disease. These results suggest that two complementary factors determine the susceptibility of brain projecting neurons to apoE deficiency: pathway-specific differences and the distance of the nerve terminals from their cell body.     

Serotonin uptake inhibitors and the prejunctional effects of serotonin on peripheral sympathetic nerves

The experiments were designed to study whether the inhibitors of the uptake of serotonin (5-HT) potentiated the prejunctional effects of 5-HT on peripheral sympathetic nerves. The effect of two selective 5-HT uptake inhibitors, citalopram and fluoxetine, were studied on the presynaptic actions of 5-HT in the cat isolated nictitating membrane and in the guinea-pig isolated atria. Frequency-effect curves to nerve stimulation and concentration-response curves to noradrenaline (NA) were performed in both preparations. The facilitation that 0.1 microM 5-HT causes on the contractile responses to nerve stimulation of the nictitating membrane of the cat was not potentiated but entirely prevented by both 0.01 microM citalopram and 1.0 microM fluoxetine. On the other hand the diminution that 1.0 microM 5-HT evokes on the chronotropic responses to nerve stimulation of guinea-pig isolated atria was not modified at all by 0.1 and 1.0 microM fluoxetine and only partially prevented by 10.0 microM fluoxetine and by 0.001 microM, 0.01 microM and 0.1 microM citalopram. This latter effect of citalopram was unrelated to the concentration employed. The 5-HT uptake inhibitors did not modify per se either the responses to nerve stimulation or the sensitivity to exogenous NA in both tissues studied. In addition, the 5-HT uptake inhibitors did not interfere with the contractile responses caused by 5-HT in the cat isolated nictitating membrane. Taken together, these observations might indicate a pharmacological rather than a physiological role for the effects of 5-HT in guinea-pig isolated atria and cat nictitating membranes. It is concluded that the 5-HT uptake inhibitors do not potentiate but even antagonize the presynaptic effects of 5-HT. Our results also show that 5-HT uptake inhibitors are more effective to interfere with the facilitation rather than with the inhibition that 5-HT causes on sympathetic responses.     

Norepinephrine release from the lung by sympathetic nerve stimulation inhibition by vagus and methacholine

A procedure to isolate the sympathetic nerve supply to the lung has been developed in the rabbit. Electrical stimulation (50V, 1ms, 10Hz) of these nerves released norepinephrine (NE) which could be measured in the outflows from lungs perfused via the pulmonary artery. On the average 19 ng NE/stimulation period were found in the perfusates. The release of NE from the lung by nerve stimulation is thereby demonstrated by direct measurement of the amine. Infusion of methacholine (1 or 10 ug/ml) and excitation of the vagus nerves inhibited the output of NE. These data suggest existence of a sympathetic-parasympathetic presynaptic balance in the lung.     

Presynaptic mechanisms of zinc effects on the neuromuscular transmission]

The effect of zinc ions on presynaptic currents and transmitter release was studied at the neuromuscular junction of the frog cutaneous pectoris muscle preparation with using an extracellular microelectrode. It has been shown that zinc (100 mkM) amplified MEPP frequency at first, but suppressed it later. Zinc affected the presynaptic spike waveform and transmitter release in a concentration-dependent manner. Depending on concentration and time of exposure zinc increased or suppressed transmitter release. Increase of transmitter release was shown to be resulted by blockade voltage gated and calcium activated potassium channels in nerve ending, leading to broad of both presynaptic spike and action potential. Strong change of presynaptic spike waveform after high concentration zinc treatment supposed that under this condition zinc depressed voltage gated calcium and sodium channel leading to decrease of transmitter release. It was concluded that the final and irreversible depression of acetylcholine release by zinc was due to alteration of whole ion conductances in nerve ending and to change of configuration of proteins included in structure of ion channels. It is discussed possible mechanisms of various effects of zinc ions at the neuromuscular synapse.