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Atropine is an established antidote in organophosphorus poisoning. It is an anticholinergic that inhibits the muscarinic actions of acetylcholine at postganglionic parasympathetic neuroeffector sites including secretary glands, smooth muscle, and CNS sites. In the literature, the cases of atropine intoxication are not uncommon. We report a case series of five cases of atropine induced psychotic disorder in patients, who manifested with delirium, hallucinations, nervousness, drowsiness, weakness, irrelevant talk, flushing along with tachycardia, and non-reactive dilated pupils suggesting possible anti-cholinergic abuse. The patients reported at the Department of Medicine-Unit II, Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, from January to June 2019. The patients were managed symptomatically by titrating down the atropine's dose, administration of benzodiazepine, and antipsychotics. "This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited".

Here, we recognise some of the extraordinary accomplishments of the partnership between Geoff Burnstock and Mollie Holman, and the everlasting impact they both made in autonomic neuroscience in Australia. Much of strength today in autonomic neuroscience can be traced back to a time when Geoff and Mollie commenced their seminal studies on autonomic neuroscience, initially at Oxford, then at The University of Melbourne in the mid 1960's. Mollie and Geoff published their first paper together, at Oxford, with their then mentor, and doyenne of smooth muscle, Professor Edith Bulbring. They did not always agree on the interpretation of their own scientific findings. Geoff was convinced early on that Adenosine triphosphate (ATP), or a related purine, was an excitatory neurotransmitter at peripheral sympathetic neuroeffector junctions. Mollie was reticent for decades. However, she began to take the notion seriously that ATP maybe a neurotransmitter, when receptors for purines were identified in the 1990's. What the partnership between Mollie and Geoff taught us in Australia was to not fear respectful criticism, but rather to be receptive to and embrace objective, collegial and constructive scientific peer-review. One of the many great legacies of Geoff and Mollie was the large number of researchers, who were fortunate disciples of their supervision, and who have now themselves gone on to make significant discoveries in autonomic and visceral neuroscience. This review summarizes some of their major legacies and represents a very personal historical perspective of the two authors, pupils respectively of Mollie and Geoff.

Robert Furchgott was first noted for research on drug–receptor theory, autonomic neuroeffector mechanisms, and vascular pharmacology/physiology. His studies on drug–receptor interactions provided important knowledge about the properties of drug receptors long before methodologies were developed to study them directly. However, Furchgott achieved an enduring legacy for recognizing the importance of endothelial cells for the relaxation of vascular smooth muscle. On the basis of his own experiments and those of others, he proposed that acetylcholine interacted with muscarinic receptors at the surface of endothelial cells to release a substance called endothelium relaxing factor. Endothelium relaxing factor was later identified as nitric oxide, a colorless, odorless gas. Furchgott’s discovery of an entirely new mechanism by which blood vessels dilate revolutionized studies on the physiology of the vascular system. His work also suggested new treatments for hypertension and heart disease, and was a key factor in the development of the anti-impotence drug sildenafil. In 1998, Robert Furchgott shared the Nobel Prize in Physiology or Medicine with Ferid Murad and Louis Ignarro.

The feeding response in the Cnidarian, hydra, consists of mouth opening, tentacle writhing, and the cessation of pacemaker-controlled tentacle and body contractions. The behavior can be induced by reduced glutathione (GSH), contained in body fluids that leak from prey impaled by hydra's cnidocysts. Mouth, tentacle, and body-contraction behavior is carried out by hydra's ectodermal and endodermal epitheliomuscular cells. Here, we present the first evidence of GSH-induced electrical activity in the hypostome and its modification by GABA and GABAB ligands. The 'heads' of hydra were ablated and the tentacles removed. Suction electrodes, positioned on the mouth, recorded electrical activity produced by GSH, contained either within the electrode, or in the surrounding bath, the mouth being shielded. Recorded impulses were characterized, according to size and temporal pattern, as small, medium and (large) pacemaker impulses. GSH applied in the bath caused a frequency increase of small and medium impulses and a decrease in pacemaker bursts. The changes in frequencies of medium and pacemaker bursts, though not obviously affected by GABA, were counteracted by blocking GABAB inhibition with phaclofen. Only the highest concentration of GSH applied at the mouth potentially decreased pacemaker frequency and potentially increased medium impulses, without affecting small impulses. GABA caused a significant increase in small and medium impulses relative to GSH which was counteracted by baclofen and/or baclofen plus phaclofen. The results indicate that considerable GSH-receptor circuitry is located in hypostomal tissue proximal to hydra's mouth, and substantiate GABA and GABAB inhibition within the neuroeffector network of the feeding response.

The kidney is extensively innervated by sympathetic nerves playing an important role in the regulation of blood pressure homeostasis. Sympathetic nerve activity is ultimately controlled by the central nervous system (CNS). Norepinephrine, the main sympathetic neurotransmitter, is released at prejunctional neuroeffector junctions in the kidney and modulates renin release, renal vascular resistance, sodium and water handling, and immune cell response. Under physiological conditions, renal sympathetic nerve activity (RSNA) is modulated by peripheral mechanisms such as the renorenal reflex, a complex interaction between efferent sympathetic nerves, central mechanism, and afferent sensory nerves. RSNA is increased in hypertension and, therefore, critical for the perpetuation of hypertension and the development of hypertensive kidney disease. Renal sympathetic neurotransmission is not only regulated by RSNA but also by prejunctional α2-adrenoceptors. Prejunctional α2-adrenoceptors serve as autoreceptors which, when activated by norepinephrine, inhibit the subsequent release of norepinephrine induced by a sympathetic nerve impulse. Deletion of α2-adrenoceptors aggravates hypertension ultimately by modulating renal pressor response and sodium handling. α2-adrenoceptors are also expressed in the vasculature, renal tubules, and immune cells and exert thereby effects related to vascular tone, sodium excretion, and inflammation. In the present review, we highlight the role of α2-adrenoceptors on renal sympathetic neurotransmission and its impact on hypertension. Moreover, we focus on physiological and pathophysiological functions mediated by non-adrenergic α2-adrenoceptors. In detail, we discuss the effects of sympathetic norepinephrine release and α2-adrenoceptor activation on renal sodium transporters, on renal vascular tone, and on immune cells in the context of hypertension and kidney disease.

Renaissance England witnessed a series of brief epidemics of a rapid and often fatal illness, the predominant feature of which was a disturbance of the autonomic nervous system. Profuse sweating was both an emblematic and ominous sign of this Sudor Anglicus. Its story is medically fascinating as well as historically noteworthy. Possible sites of pathological involvement include the hypothalamus, serotonergic neurons in the brainstem or spinal cord, autonomic ganglia, peripheral sympathetic nerves, neuroeffector junctions, or eccrine glands. Of candidate etiologic agents, a virus is most likely, given the seasonal variation, geographic clustering, and pattern of spread of the epidemics. Hantaviruses, enteroviruses, influenza, and others provide clinical comparisons, but a definitive match with known viruses has remained elusive.

Key points The present study demonstrates, by in vitro and in vivo analyses, the novel concept that signal transmission between sympathetic neurons and the heart, underlying the physiological regulation of cardiac function, operates in a quasi-synaptic fashion. This is a result of the direct coupling between neurotransmitter releasing sites and effector cardiomyocyte membranes. Abstract Cardiac sympathetic neurons (SNs) finely tune the rate and strength of heart contractions to match blood demand, both at rest and during acute stress, through the release of noradrenaline (NE). Junctional sites at the interface between the two cell types have been observed, although whether direct neurocardiac coupling has a role in heart physiology has not been clearly demonstrated to date. We investigated the dynamics of SN/cardiomyocyte intercellular signalling, both by fluorescence resonance energy transfer-based imaging of cAMP in co-cultures, as a readout of cardiac β-adrenergic receptor activation, and in vivo, using optogenetics in transgenic mice with SN-specific expression of Channelrhodopsin-2. We demonstrate that SNs and cardiomyocytes interact at specific sites in the human and rodent heart, as well as in co-cultures. Accordingly, neuronal activation elicited intracellular cAMP increases only in directly contacted myocytes and cell-cell coupling utilized a junctional extracellular signalling domain with an elevated NE concentration. In the living mouse, optogenetic activation of cardiac SNs innervating the sino-atrial node resulted in an instantaneous chronotropic effect, which shortened the heartbeat interval with single beat precision. Remarkably, inhibition of the optogenetically elicited chronotropic responses required a high dose of propranolol (20-50 mg kg-1 ), suggesting that sympathetic neurotransmission in the heart occurs at a locally elevated NE concentration. Our in vitro and in vivo data suggest that the control of cardiac function by SNs occurs via direct intercellular coupling as a result of the establishment of a specific junctional site.

Antipsychotic drugs are the mainstay of psychotic disorders. The 'typical' antipsychotic agents are commonly employed for the positive symptoms of schizophrenia, though at an expense of extrapyramidal side effects (EPS). In the present study, we employed haloperidol (HP)-induced catalepsy model in mice to evaluate the role of adenosine receptor antagonist and cyclooxygenase (COX) enzyme inhibitor in the amelioration of EPS. HP produced a full blown catalepsy, akinesia and a significant impairment in locomotion and antioxidant status. Pre-treatment with COX inhibitor; naproxen (NPx) and adenosine receptor antagonist; caffeine (CAF), showed a significant impact on HP-induced cataleptic symptoms. Adenosine exerts pivotal control on dopaminergic receptors and is also involved in receptor internalization and recycling. On the other hand, prostaglandins (PGs) are implicated as neuro-inflammatory molecules released due to microglial activation in both Parkinson's disease (PD) and antipsychotics-induced EPS. The involvement of these neuroeffector molecules has led to the possibility of use of CAF and COX inhibitors as therapeutic approaches to reduce the EPS burden of antipsychotic drugs. Both these pathways seem to be interlinked to each other, where adenosine modulates the formation of PGs through transcriptional modulation of COXs. We observed an additive effect with combined treatment of NPx and CAF against HP-induced movement disorder. These effects lead us to propose that neuromodulatory pathways of dopaminergic circuitry need to be explored for further understanding and utilizing the full therapeutic potential of antipsychotic agents.

There is introductory information about non-synaptic transmission at sympathetic neuroeffector junctions and sympathetic nerve cotransmission utilizing noradrenaline and ATP as cotransmitters. Then the organzation and location of sympathetic nerves in different sites in the kidney are described, including renal arteries, juxtaglomerular arterioles and renal tubules. Sympathetic nervous control of glomerular filtration rate and of renin secretion are discussed. Evidence, obtained largely from experiments on animals, for sympathetic nerve modulation of the transport of water, sodium and other ions in the collecting duct of the nephron is described. Finally, there is coverage of the roles of sympathetic nerves in renal diseases, including hypertension, diabetes, hypothyroidism and ischaemia.

This chapter reviews the anatomy of the circulation in nerves with emphasis on its regulation by nonadrenergic, noncholinergic neuroeffector mechanisms. Endoneurial vasa nervorum branch symmetrically and repeatedly and consist only of capillaries. Vasa nervorum are composed of the same elements as other blood vessels, but their ultrastructural features are less well defined. Vasa nervorum are encircled by connective tissue containing substantial extracellular space. The permeability of vasa nervorum regulates the passage of metabolites, toxins, and other substances to nerves, and it is therefore important in blood-nerve barrier function in health and disease. The innervation of vasa nervorum and the role of neurotransmitters in nervi nervorum has been largely ignored. Serotoninergic innervation of vasa and nervi nervorum may therefore be important in maintaining the integrity of the blood-nerve barrier and in hom-eostatically regulating the peripheral and cranial nerve environment. Clinical and experimental observations show a relationship between blood vessels supplying blood to nerves and peripheral nerve dysfunction in pathological states.

Local anesthetics, corticosteroids, and botulinum toxin are the drugs widely used in interventional headache management. Local anesthetics are used in peripheral nerve blocks, trigger point injections, and sphenopalatine ganglion block. Local anesthetics preferentially bind to voltage-gated sodium channels when they are in the inactivated state, prolong the duration of inactivation, prevent the firing and propagation of the action potentials, and consequently block sensory information. Analgesia longer than the anesthetic effect could be achieved with peripheral nerve blocks due to central pain modulation. The most widely used local anesthetics for peripheral nerve blocks and trigger point injections are bupivacaine and lidocaine. The duration of the analgesia caused by a peripheral nerve block is prolonged by adding steroids to local anesthetics. Corticosteroids show their effects in interventional headache management via their anti-inflammatory, weak membrane stabilizer properties and by inhibiting unmyelinated C-fiber transmission. Botulinum toxin, approved for chronic migraine, prevents acetylcholine release at the neuromuscular junction or neuroeffector junctions by cleaving one of the SNARE proteins and by rendering this protein useless. A suggested mechanism for the efficacy of BoNT in chronic migraine is the inhibition of peripheral sensitization and indirectly reduced central sensitization. BoNT inhibits the release of neuropeptides such as substance P and calcitonin gene-related peptide that are associated with pain. It is essential to follow the PREEMPT onabotulinum toxin A injection protocols of fixed-site/fixed-dose or follow-the-pain to achieve maximum efficacy in chronic migraine.

Purine nucleotides and nucleosides act as extracellular messengers, according to the concept of purinergic signaling first proposed over 30 years ago by Burnstock. Since then, receptor subtypes for adenosine-selective (P1 receptors) and purine and pyrimidine selective (P2 receptors) have been cloned and characterized. Almost every tissue in the body expresses P1 and/or P2 receptors. The number of different receptor subtypes, particularly for P2X and P2Y receptors is large, mediating many different short- and long-term (trophic) responses upon activation. Individual cell types or tissues often express multiple subtypes of P1 and P2 receptors that can act separately, antagonistically or synergistically.

The structure of the autonomic neuroeffector junction is described. The essential features are: that the terminal portions of autonomic nerve fibers are varicose, transmitters being released en passage from varying distances from the effector cells; although there is no structural postjunctional specialization on effector cells, receptors for neurotransmitters accumulate on cell membranes at close junctions; muscle effectors are bundles rather than single smooth muscle cells and are connected by gap junctions which allow electronic spread of activity between cells. A multiplicity of transmitters are utilized by autonomic nerves, and cotransmission occurs often involving synergistic actions of the cotransmitters, although pre- and postjunctional neuromodulation of neurotransmitter release also takes place. Cotransmission with sympathetic, parasympathetic, sensory–motor, and intramural neuroeffector junctions is described. The plasticity of neurotransmitter and receptor expression in development and aging, following trauma, and in disease are discussed.

Skin sympathetic nerve activity (SSNA) is microneurographically recorded from the skin nerve fascicle in the peripheral nerves with properties of an irregular, pulse asynchronous burst with respiratory variation, followed by sweating and/or vasoconstriction, elicited by mental stress and arousal stimuli. It comprises sudomotor and vasoconstrictor nerve activities as well as vasodilator ones. SSNA function in thermoregulation in humans, however, is also elicited by mental stress or cognition. SSNA is lowest at thermoneutral temperature and enhanced in the presence of ambient warm and cool air. Burst amplitude is well correlated to sweat rate change or skin blood flow reduction rate. The clinical application of SSNA comprises the following: (1) clarification of sweating events, (2) clarification and diagnosis of anhidrosis or hyperhidrosis, (3) clarification of thermoregulatory function and diagnosis of thermoregulatory disorder, (4) clarification of pathophysiology and diagnosis of vascular disorders, (5) clarification of the relationship between cognitive function and SSNA, and (6) determination of pharmacological effects attributable to change in neuroeffector responses. Lastly, SSNA’s significance as a feedforward thermoregulatory tool is discussed since SSNA contributes more to rapid thermoregulatory response than thermoregulation using convectional thermotransmission. Especially feedforward thermoregulatory sweating response is estimated to be highly phylogenetic than vasoconstrictive response.

blood flow distribution at rest and during exercise is intricately controlled by centrally driven neuroeffector mechanisms and circulating hormones (particularly epinephrine), local autacoids, and metabolites, all superimposed on the inherent or “myogenic” reactivity of the arterial smooth

This review is concerned with understanding how vasodilation initiated from local sites in the tissue can spread to encompass multiple branches of the resistance vasculature. Within tissues, arteriolar networks control the distribution and magnitude of capillary perfusion. Vasodilation arising from the microcirculation can ‘ascend’ into feed arteries that control blood flow into arteriolar networks. Thus distal segments of the resistance network signal proximal segments to dilate and thereby increase total oxygen supply to parenchymal cells. August Krogh proposed that innervation of capillaries provided the mechanism for a spreading vasodilatory response. With greater understanding of the ultrastructural organization of resistance networks, an alternative explanation has emerged: Electrical signaling from cell to cell along the vessel wall through gap junctions. Hyperpolarization originates from ion channel activation at the site of stimulation with the endothelium serving as the predominant cellular pathway for signal conduction along the vessel wall. As hyperpolarization travels, it is transmitted into surrounding smooth muscle cells through myoendothelial coupling to promote relaxation. Conducted vasodilation encompasses greater distances than can be explained by passive decay and understanding such behavior is the focus of current research efforts. In the context of athletic performance, the ability of vasodilation to ascend into feed arteries is essential to achieving peak levels of muscle blood flow. Conducted vasodilation is tempered by sympathetic neuroeffector signaling when governing muscle blood flow at rest and during exercise. Impairment of conduction during aging and in diseased states can limit physical work capacity by restricting muscle blood flow.

Control of gastrointestinal (GI) movements by enteric motoneurons is critical for orderly processing of food, absorption of nutrients and elimination of wastes. Work over the past several years has suggested that motor neurotransmission is more complicated than simple release of transmitter from nerve terminals and binding of receptors on smooth muscle cells. In fact the ‘neuro-effector’ junction in the tunica muscularis might consist of synaptic-like connectivity with specialized cells, and contributions from multiple cell types in integrated post-junctional responses. Interstitial cells of Cajal (ICC) were proposed as potential mediators in motor neurotransmission based on reduced post-junctional responses observed in W mutants that have reduced populations of ICC. More recent studies on W mutants have contradicted the original findings, and suggested that ICC may not be significant players in motor neurotransmission. This review examines the evidence for and against the role of ICC in motor neurotransmission and outlines areas for additional investigation that would help further resolve this controversy.

Incidence and rate of cardiovascular disease differ between men and women across the life span. Although hypertension is more prominent in men than women, there is a group of vasomotor disorders [i.e. Raynaud’s disease, postural orthostatic tachycardia syndrome (POTS) and vasomotor symptoms (hot flashes) of menopause and migraine] with a female predominance. Both sex and hormones interact to modulate neuroeffector mechanisms including integrated regulation of the Sry gene and direct effect of sex steroid hormones on synthesis, release and disposition of monoamine neurotransmitters, and distribution and sensitivity of their receptors in brain areas associated with autonomic control. The interaction of the sex chromosomes and steroids also modulates these effector tissues, that is, the heart, vascular smooth muscle and endothelium. While involvement of central serotonergic centers has been studied in regard to mood disorders such as depression, their contribution to cardiovascular risk is gaining attention. Studies are needed to further evaluate how hormonal treatments and drugs used to modulate adrenergic and serotonergic activity affect progression and risk for cardiovascular disease in men and women.

β-Adrenoceptor antagonists are used widely to reduce cardiovascular sympathetic tone, but withdrawal is accompanied by sympathetic hyperactivity. Receptor supersensitivity accounts for some but not all aspects of this withdrawal syndrome. Therefore, we investigated effects of β-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective β-blocker propranolol and the β1-antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, β-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramine-induced mobilization of norepinephrine stores produced elevated ventricular contractility consistent with enhanced sympathetic neuroeffector properties. In addition, rats undergoing discontinuation showed exaggerated increases in mean arterial pressure in response to air puff or noise startle. In sympathetic neuronal cell cultures, both propranolol and metoprolol increased axon outgrowth but the β2-blocker ICI 118551 did not. Norepinephrine synthesis suppression by α-methyl-p-tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via β1-adrenoceptors. Immunohistochemistry revealed β1-adrenoceptor protein on sympathetic axon terminations. In rats with coronary artery ligation, propranolol reversed heart failure-induced ventricular myocardial sympathetic axon depletion, but did not affect infarct-associated sympathetic hyperinnervation. We conclude that sympathetic neurons possess β1-autoreceptors that negatively regulate axon outgrowth. Chronic β-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to β-blocker withdrawal syndrome.

This communication represents personal perspectives of recent development in the newly evolved areas in vascular signaling mechanisms at the anatomical level of vascular walls from outside in, that is, from perivascular adventitial side to effectuate the control of vascular reactivity. Since half a century ago, the focus of interest in vascular biology has been confined primarily to the study of the excitation-contraction coupling of vascular smooth muscle (VSM) as well as neuroeffector mechanisms. During the past 3 decades, considerable advancement in the understanding of vascular signaling has been made via the discovery of endothelium-derived relaxation factors (EDRF), endothelium-derived hyperpolarizing factors (EDHF) and endothelium-derived contracting factors (EDCF). The discovery of nitric oxide (NO) as a major cellular messenger has also helped open up another huge area of research in oxidative stress and vascular diseases. In the past decade, concepts on vascular wall signaling have been extended from vascular endothelial cells and then translated to the other seemingly inert cellular components, such as perivascular adipocytes and adventitial fibroblasts. Growing body of evidences show that these cellularities contribute to both functional as well as structural integrity in vasculature with significant pathophysiological implications.

Objective/background Signals for the expression of EGF, TGFα and related proteins are largely unknown. Having shown earlier, that activation of the afferent sensory nervous system by capsaicin induced epithelial cell proliferation and TGFα expression in vivo the aim of this study was to demonstrate, that neurotransmitters of the afferent sensory nervous system induce TGFα expression via mast cells and fibroblasts. Results A significant increase in TGFα-mRNA and protein expression was detected in epithelial cells exposed to supernatants of CGRP-stimulated mast cells and SP-stimulated fibroblasts. Epithelial cell proliferation was only detected in epithelial cells exposed to supernatants of CGRP-stimulated mast cells but not in epithelial cells exposed to supernatants of SP-stimulated fibroblasts. TGFβ mRNA expression was increased in epithelial cells exposed to fibroblasts but not to mast cells. No increase in EGF-receptor expression was detected in epithelial cells exposed to either fibroblast or mast cell supernatants. Conclusion Neurotransmitters of the afferent sensory nervous system induce TGFα expression in epithelial cells mediated by mast cells and fibroblasts. Release of CGRP and SP from neuroeffector junctions is an important signal for the TGFα expression after mucosal injury. Mucosal expression of TGFα may contribute to the protective effects of the sensory nervous system after mucosal injury.

In order to allow precise regulation of bodily functions, the activity of the autonomic nervous system must be precisely regulated. The traditional model concerning the regulation of norepinephrine and acetylcholine release in target tissues suggests that the activities of the efferent arms of the autonomic nervous system are more or less independent of each other. However, plenty of experimental and clinical studies have demonstrated the presence of multiple interactions between the sympathetic and parasympathetic nervous system that are mediated through several pathways and mechanisms at both central and peripheral levels of the neuraxis. Interactions within the central nervous system are mediated predominantly by neurons within the nucleus of the solitary tract and paraventricular hypothalamic nucleus. Peripheral interactions are based on the morphological-functional organization of the sympathetic and parasympathetic pathways at the levels of the sympathetic prevertebral ganglia or neuroeffector connections. Furthermore, evidence suggests that neuroeffector connections may be realized at the axo-axonal, presynaptic, postsynaptic, and post-receptor levels. Alterations in interactions between the sympathetic and parasympathetic nervous system can lead to unbalanced autonomic activities, which may influence the development of various disorders, including cardiovascular, inflammatory, metabolic, neurological, and psychiatric diseases. The aim of this article is to illustrate the complexity of interaction between the sympathetic and parasympathetic nervous systems and to describe the role of these interactions in the heart, adrenal medulla, and vagal trunk.

We studied hypertension-associated changes in prejunctional alpha(2) adrenergic receptor (alpha(2)-AR) function using amperometry to monitor in vitro norepinephrine (NE) measured as oxidation currents. Vasoconstriction was measured using video imaging. NE release was induced by electrical stimulation of sympathetic nerves associated with mesenteric arteries (MA) and veins (MV) of sham and DOCA-salt hypertensive rats. NE oxidation currents were larger in DOCA-salt compared to sham MA; there were no differences between currents in sham and DOCA-salt MV. Increases in NE oxidation currents followed a multi-exponential time course in sham MA. In DOCA-salt MA and sham and DOCA-salt MV, the time course was mono-exponential. Yohimbine (alpha(2)-AR antagonist, 1 microM), caused a mono-exponential increase in NE oxidation currents in sham and DOCA-salt MA. Yohimbine increased NE oxidation currents and constrictions more in sham compared to DOCA-salt MA and compared to MV. UK 14,304 (alpha(2)-AR agonist, 1.0 microM), reduced currents less in DOCA-salt MA and sham and DOCA-salt MV compared to sham MA. Prazosin (alpha(1)-AR antagonist, 0.1 microM) did not alter NE oxidation currents. Prazosin inhibited constrictions more in DOCA-salt compared to sham MA and almost completely blocked constrictions in sham and DOCA-salt MV. Prazosin-resistant constrictions in MA were blocked by the P2 receptor antagonist, PPADS (10 microM). Prejunctional alpha(2)-ARs modify NE concentrations near neuroeffector junctions in MA and MV. alpha(2)-AR function is most prominent in MA and is impaired in DOCA-salt MA but not MV. Purinergic transmission predominates in sham MA. NE is the dominant vasoconstrictor in DOCA-salt MA and sham and DOCA-salt MV.

It is acknowledged that neurotransmission in the mouse vas deferens is predominantly mediated by ATP and noradrenaline (NA) released from sympathetic nerves while cholinergic transmission in the rodent vas deferens is often overlooked despite early literature. Recently we have characterized a cholinergic component of neurogenic contraction of mouse isolated vas deferens. In the present paper, by confocal imaging of Ca(2+) dynamics we detected acetylcholine (ACh) action at muscarinic cholinergic neuroeffector junctions at high-resolution. Experiments were carried out in the presence of prazosin (100 nM) and alpha,beta methylene ATP (alpha,beta-MeATP) (1 microM) to inhibit responses to NA and ATP respectively. Exogenous ACh (10 microM) elicited Ca(2+) transients, an effect blocked by the muscarinic receptor antagonist, cyclopentolate (1 microM). Ca(2+) transients were evoked by electrical stimulation of intrinsic nerves in the presence of the cholinesterase inhibitor neostigmine (10 microM). Stimulation produced a marked increase in the frequency and number of Ca(2+) transients. Cyclopentolate reduced the frequency of occurrence of spontaneous and evoked events to control levels. The alpha(2)-adrenoceptor antagonist yohimbine (300 nM) did not affect the spontaneous Ca(2+) transients, but increased the frequency of occurrence of evoked transients, an effect inhibited by cyclopentolate. The postjunctional effects of neuronally-released ACh are limited by the action of cholinesterase. Release of ACh appears to be tonically inhibited by NA released from sympathetic nerve terminals through action at prejunctional alpha(2)-adrenoceptors. Tetrodotoxin (TTX, 300 nM) abolished the nerve-evoked Ca(2+) events, with no effect on Ca(2+) transients elicited by exogenous ACh. In conclusion, the presence of spontaneous and evoked cholinergic Ca(2+) transients in smooth muscle cells of the mouse isolated vas deferens has been revealed. These events are mediated by ACh acting at M(3) muscarinic receptors. This action stands in marked contrast to the lack of effect of neuronally-released NA on smooth muscle Ca(2+) dynamics in this tissue.

Determining whether ATP and noradrenaline are released from the same vesicle at mature autonomic neuroeffector junctions is challenging because of the difficulty of simultaneously detecting the packeted release of these neurotransmitters. Contraction, overflow and electrophysiology experiments all show that both ATP and noradrenaline are released following field stimulation (although the ratio might vary) from autonomic nerves in tissues including the vas deferens, rat tail artery and mesenteric artery. The occurrence of purinergic neuroeffector Ca2+ transients (NCTs) has been used to detect the packeted release of the neurotransmitter ATP acting on postjunctional P2X receptors to cause Ca2+ influx. Neuroeffector Ca2+ transients can also be used to detect the local effects of noradrenaline through its α2-adrenoceptor-mediated prejunctional autoinhibitory effects on nerve terminal Ca2+ concentration and the probability of exocytosis (measured by counting NCTs). Evidence is presented that exocytosis from sympathetic varicosities does not occur in a manner independent of the history of that varicosity, but rather that the release of a packet of ATP transiently suppresses (or predicts the transient suppression of) subsequent release. This could arise by autoinhibition (by the prejunctional action of noradrenaline or purines) or due to a transient shortage of vesicles readily available for release. In summary, two high-resolution approaches are proposed to measure the intermittent release of packets of neurotransmitter: (1) local transient suppression of nerve terminal Ca2+ transients; and (2) the local and transient inhibition of NCTs to infer local autoinhibition, hence transmitter release. Such approaches may allow the packeted corelease of ATP and noradrenaline to be investigated without the need to measure both neurotransmitters directly.

Background and purpose: The antidysrhythmic bretylium is useful experimentally because it selectively abolishes neurotransmitter release from sympathetic peripheral nerve terminals. Its mechanism of action seemed settled, but recent results from optical monitoring of single terminals now suggests a new interpretation. Experimental approach: Orthograde transport of a dextran-conjugated Ca2+ indicator to monitor Ca2+ in nerve terminals of mouse isolated vas deferens with a confocal microscope. In some experiments, local neurotransmitter release was detected by monitoring neuroeffector Ca2+ transients (NCTs) in adjacent smooth muscles, a local measure of purinergic transmission. Sympathetic terminals were identified with catecholamine fluorescence (UV excitation) or post-experiment immunohistochemistry. Key results: Bretylium (10 μM) abolished NCTs at 60/61 junctions over the course of 2 h, indicating effective abolition of neurotransmitter release. However, bretylium did not abolish the field stimulus-induced Ca2+ transient in most nerve terminals, but did increase both action potential delay (by 2±0.4 ms) and absolute refractory period (by 4±2 ms). Immunohistochemistry demonstrated that 85–96% of terminals orthogradely filled with a dextran-conjugated fluorescent probe contained Neuropeptide Y (NPY). A formaldehyde–glutaraldehyde-induced catecholamine fluorescence (FAGLU) technique was modified to allow sympathetic terminals to be identified with a Ca2+ indicator present. Most terminals contained catecholamines (based on FAGLU) or secrete ATP (as NCTs in adjacent smooth muscle cells are abolished). Conclusions and implications: Bretylium can inhibit neurotransmitter release downstream of Ca2+ influx without abolishing the nerve terminal action potential. Bretylium-induced increases in the absolute refractory period permit living sympathetic terminals to be identified. British Journal of Pharmacology (2008) 153, 831–839; doi:10.1038/sj.bjp.0707623; published online 10 December 2007

In this issue of Circulation , Fung and coworkers1 report associations between hand venous responses to the indirectly acting sympathomimetic amine tyramine and single nucleotide polymorphisms (SNPs) of genes encoding particular proteins related to the synthesis, release, reuptake, and metabolism of catecholamines. The importance of these associations lies in their illustrating how genotypic differences may contribute to phenotypic differences in circulatory functions in healthy adults via sympathetic neuroeffector mechanisms. More generally, identification of SNPs related to catecholamine systems may provide insights into the pathophysiology, diagnosis, and treatment of a variety of cardiovascular disorders.2 Article p 517 To provide perspective about these findings, this editorial compares and contrasts tyramine-induced changes and sympathetic neuroeffector functions; discusses strengths and weaknesses of the dorsal hand vein model; emphasizes the potential of clinical catecholamine neurochemistry to link genotype with cardiovascular phenotype; and conveys a viewpoint on observational versus hypothesis-driven genotyping. Tyramine produces vasoconstriction via release of endogenous norepinephrine, the main neurotransmitter of the sympathetic nervous system mediating cardiovascular responses to stressors. The authors relied on the local vascular actions of tyramine as an indirectly acting sympathomimetic amine to draw inferences about sympathetic neuroeffector functions. Mechanisms of tyramine-induced norepinephrine release differ in several respects from those of sympathetically mediated norepinephrine release. The Figure depicts some of these differences. Figure. Mechanisms of sympathetically mediated and tyramine-induced norepinephrine release. NE indicates norepinephrine; TYR, tyramine; AR, aldehyde reductase; VMAT, vesicular monoamine transporter; and MAO, monoamine oxidase. First, tyramine releases norepinephrine in a calcium-independent manner3 that is not exocytotic,4 in contrast to calcium-dependent exocytosis in response to sympathetic nerve stimulation. Tyramine displaces norepinephrine from storage vesicles, possibly by alkalinizing them.5 Because most of the vesicles would not be expected to be in communication with the extracellular fluid under resting conditions, most of the displaced norepinephrine …

Gastroenteropathy causes considerable morbidity in patients with diabetes mellitus and represents a major healthcare burden. Current treatments are largely symptomatic and frequently ineffective. Development of new therapeutic options is hampered by poor understanding of the underlying pathomechanisms. Experimental studies and sparse human data indicate that diabetic gastroenteropathy is multifactorial and involves not only parasympathetic and sympathetic autonomic nerves, but also enteric neurons, smooth muscle cells and interstitial cells of Cajal (ICC). ICC are mesenchymal cells that occur throughout the muscular coat of the gastrointestinal tract and provide functions critical for normal gastrointestinal motility including generation and propagation of electrical slow waves and mediation of bidirectional communication between the autonomic nervous system and smooth muscle cells. Through these functions, and in concert with other cell types of the gastrointestinal muscles, ICC support basic gastrointestinal functions such as digestion, absorption and waste removal. Loss or dysfunction of ICC in various dysmotilities and their animal models has been shown to lead to gastric dysrhythmias, gastroparesis, slow intestinal transit, impaired neuroeffector mechanisms and altered visceral afferent signalling that are considered hallmarks of diabetic gastroenteropathy. These findings and an increasing body of evidence indicating disruptions of ICC networks in diabetes suggest that the loss of ICC in this disorder is probably of functional significance and could even be a major pathogenetic factor. Future research should focus on the identification of the molecular and cellular mechanisms underlying ICC loss in diabetes and the translation of the experimental findings into treatments.

As arteries are resistance blood vessels while veins perform a capacitance function, it might be expected that sympathetic neural control of arteries and veins would differ. The function of sympathetic nerves supplying mesenteric arteries (MA) and veins (MV) in rats was investigated using in vitro continuous amperometry with a carbon fibre microelectrode and video imaging. We simultaneously measured noradrenaline (NA) overflow at the blood vessel adventitial surface and vasoconstriction evoked by electrical stimulation of perivascular sympathetic nerves. Sympathetic nerve arrangement was studied using glyoxylic acid-induced fluorescence of NA. We found that: (i) there were significant differences between MA and MV in the arrangement of sympathetic nerves; (ii) frequency–response curves for NA overflow and vasoconstriction for MV were left-shifted compared to MA; (iii) the P2X receptor antagonist, pyridoxal-phosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS, 10 μm), reduced constrictions in MA but not in MV while the α1-adrenergic receptor antagonist, prazosin (0.1 μm), blocked constrictions in MV but not in MA; (iv) NA overflow for MA was enhanced by the α2-adrenergic receptor antagonist, yohimbine (1.0 μm), and attenuated by the α2-adrenergic receptor agonist, UK 14,304 (1.0 μm), while yohimbine and UK 14,304 had little effect in MV; (v) cocaine (10 μm) produced larger increases in NA overflow in MA than in MV; (vi) UK 14,304 constricted MV but not MA while yohimbine reduced constrictions in MV but not MA. We conclude that there are fundamental differences in sympathetic neuroeffector mechanisms in MA and MV, which are likely to contribute to their different haemodynamic functions.

The parasympathetic (PNS) and sympathetic (SNS) and nervous systems densely innervate the exocrine pancreas. Efferent PNS pathways, consisting of central dorsal motor nucleus of the vagus (DMV) and peripheral pancreatic neurons, stimulate exocrine secretion. The DMV integrates cortical (olfactory, gustatory) and gastric, and intestinal vagal afferent input to determine central PNS outflow during cephalic, gastric and intestinal phases of exocrine secretion. Pancreatic neurons integrate DMV input with peripheral enteric, sympathetic, and, possibly, afferent axon reflexes to determine final PNS input to all exocrine effectors. Gut and islet hormones appear to modulate both central and peripheral PNS pathways. Preganglionic sympathetic neurons in the intermediolateral (IML) column of the spinal cord receive inputs from brain centers, some shared with the PNS, and innervate postganglionic neurons, mainly in prevertebral ganglia. Sympathetic innervation of the exocrine pancreas is primarily indirect, and inhibits secretion by decreasing blood flow and inhibiting transmission in pancreatic ganglia. Interactions between SNS and PNS pathways appear to occur in brain, spinal cord, pancreatic and prevertebral ganglia, and at neuroeffector synapses. Thus, the PNS and SNS pathways regulating the exocrine pancreas are directly or indirectly antagonistic at multiple sites: the state of exocrine secretion reflects the balance of these influences. Despite over a century of study, much remains to be understood about the connections of specific neurons forming pancreatic pathways, their processes of neurotransmission, and how disruption of these pathways contributes to pancreatic disease.

The ultrastructural, histochemical, immunocytochemical, biochemical, molecular, behavioral and physiological evidence for non-peptidergic and peptidergic chemical neurotransmission in the Anthozoa, Hydrozoa, Scyphozoa and Cubozoa is surveyed. With the possible exception of data for the catecholamines and peptides in some animals, the set of cumulative data - the evidence from all methodologies - is incomplete. Taken together, the evidence from all experimental approaches suggests that both classical fast (acetylcholine, glutamate, GABA, glycine) and slow (catecholamines and serotonin) transmitters, as well as neuropeptides, are involved in cnidarian neurotransmission. Ultrastructural evidence for peptidergic, serotonergic, and catecholaminergic synaptic localization is available, but the presence of clear and dense-cored synaptic vesicles also suggests both fast and slow classical transmission. Immunocytochemical studies, in general, reveal a continuous, non-localized distribution of neuropeptides, suggesting a neuromodulatory role for them. Immunocytochemical and biochemical studies indicate the presence of glutamate, GABA, serotonin, catecholamines (and/or their receptors), RFamides, nitric oxide and eicosanoids in cnidarian neurons and tissues. Gene sequences for peptidergic preprohormones have been reported; putative gene homologies to receptor proteins for vertebrate transmitters have been found in Hydra. Behavioral and physiological studies implicate classical transmitters, neuropeptides, eicosanoids and nitric oxide in the coordination of the neuroeffector systems.

Infusion of 5-hydroxytryptamine (5 HI) in conscious rats results in a sustained (up to 30 days) fall in blood pressure. This is accompanied by an increase in splanchnic blood flow. Because the splanchnic circulation is regulated by the sympathetic nervous system, we hypothesized that 5-HT would: 1) directly reduce sympathetic nerve activity in the splanchnic region; and/or 2) inhibit sympathetic neuroeffector function in splanchnic blood vessels. Moreover, removal of the sympathetic innervation of the splanchnic circulation (celiac ganglionectomy) would reduce 5-HT-induced hypotension. In anaestherized Sprague-Dawley rats, mean blood pressure was reduced from 101 +/- 4 to 63 +/- 3 mm Hg during slow infusion of 5-HT (25 mu g/kg/min, iv). Pre- and postganglionic splanchnic sympathetic nerve activity were unaffected during 5-HT infusion. In superior mesenteric arterial rings prepared for electrical field stimulation, neither 5-HT (3, 10, 30 nM), the 5-HT1B receptor agonist CP 93129 nor 5-HT1/7 receptor agonist 5-carboxamidotryptamine inhibited neurogenic contraction compared to vehicle. 5-HT did not inhibit neurogenic contraction in superior mesenteric venous rings. Finally, celiac ganglionectomy did not modify the magnitude of fall or time course of 5-HT-induced hypotension when compared to animals receiving sham ganglionectomy. We conclude it is unlikely 5-HT interacts with the sympathetic nervous system at the level of the splanchnic preganglionic or postganglionic nerve, as well as at the neuroeffector junction, to reduce blood pressure. These important studies allow us to rule out a direct interaction of 5-HT with the splanchnic sympathetic nervous system as a cause of the 5-HT-induced fall in blood pressure. (C) 2015 Elsevier B.V. All rights reserved.

In 1888, Ramon y Cajal suggested that the contacts between the axon terminals of a neuron and the dendrites or the perikaryon of another neuron are the points at which information flows from one neuron to the other. The term synapse was introduced by Sherrington (1897) to describe these zones of contact between neurons, specialized in the transmission of information. In fact, the term ‘synapse’ is not used exclusively to describe connections between neurons (interneuronal connections) but also those between neurons and effector cells such as muscular and glandular cells (neuroeffector synapses) and those between receptive cells and neurons. These contacts are the points where the information is transmitted from one cell to the other: synaptic transmission. According to morphological and functional criteria, there are various types of synapses, including chemical, electrical and mixed types.

A new method of making preparations was used to analyse the neuroeffector connections of the paired giant neurons of the African snail Achatina fulica. These neurons were found to induce postsynaptic potentials in the muscles of the mantle, heart, the wall of the pulmonary cavity, and the muscular elements of the renal complex, the pericardium, the sexual apparatus, the walls of the cerebral arteries, the filaments of the columellar muscles, the wall of the abdomen, and the tentacle retractor muscles. Rhythmic neuron activity led to the development of marked facilitation and long-term potentiation of synaptic potentials. The possible significance of the multiple neuroeffector connections of giant neurons is discussed.

The formation of somatic neuromuscular junctions in skeletal muscle is regulated by an extracellular matrix protein called agrin. Here, we have examined the expression and localization of agrin during development of the rodent urinary bladder, as a first step to examining its possible role at autonomic neuroeffector junctions in smooth muscle. We have found that agrin is expressed on the surface of developing smooth muscle cells and in the basement membrane underlying the urothelium. More importantly, agrin is progressively concentrated at parasympathetic varicosities during postnatal development and is present at virtually all junctions in mature muscle. Reverse transcription/polymerase chain reaction analysis has shown that pelvic ganglion neurons that innervate the bladder express LN/z8 agrin, whereas bladder smooth muscle expresses LN/z- agrin. Together, these results demonstrate that nerve and/or muscle agrin becomes localized at cholinergic parasympathetic varicosities in smooth muscle, where it could play a role in the maturation of the neuroeffector junction.

The α-1 adrenergic receptors (α 1 ARs) are critical in sympathetically mediated vasoconstriction. The specific role of each α 1 AR subtype in regulating vasoconstriction remains highly controversial. Limited pharmacological studies suggest that differential α 1 AR responses may be the result of differential activation of junctional versus extrajunctional receptors. We tested the hypothesis that the α 1B AR subtype is critical in mediating sympathetic junctional neurotransmission. We measured in vivo integrated cardiovascular responses to a hypotensive stimulus (induced via transient bilateral carotid occlusion [TBCO]) in α 1B AR knockout (KO) mice and their wild-type (WT) littermates. In WT mice, after dissection of the carotid arteries and denervation of aortic baroreceptor buffering nerves, TBCO produced significant pressor and positive inotropic effects. Both responses were markedly attenuated in α 1B AR KO mice (change systolic blood pressure 46±8 versus 11±2 mm Hg; percentage change in the end-systolic pressure-volume relationship [ESPVR] 36±7% versus 12±2%; WT versus KO; P 1 AR mesenteric microvascular contractile responses to endogenous norepinephrine (NE; elicited by electrical field stimulation 10 Hz) was markedly depressed in α 1B AR KO mice compared with WT (12.4±1.7% versus 21.5±1.2%; P 1B AR KO and WT mice (22.4±7.3% versus 33.4±4.3%; NS). Collectively, these results demonstrate a critical role for the α 1B AR in baroreceptor-mediated adrenergic signaling at the vascular neuroeffector junction. Moreover, α 1B ARs modulate inotropic responses to baroreceptor activation. The critical role for α 1B AR in neuroeffector regulation of vascular tone and myocardial contractility has profound clinical implications for designing therapies for orthostatic intolerance.

The historical role of noradrenaline as the predominant sympathetic neurotransmitter in vascular neuroeffector junctions has matured to include ATP and the modulator action of neuropeptide Y (NPY). Numerous studies with isolated blood vessels rings demonstrate the presence of key enzymes responsible for the synthesis of ATP, noradrenaline and NPY, their co-storage, and their electrically evoked release from sympathetic perivascular nerve terminals. Functional assays coincide to demonstrate the integral role of these neurochemicals in sympathetic reflexes. In addition, the detection of the diverse receptor populations for ATP, noradrenaline and NPY in blood vessels, either in the smooth muscle, endothelial cells or nerve endings, further contribute to the notion that sympathetic vascular reflexes encompass the orchestrated action of the noradrenaline and ATP, and their modulation by NPY. The future clinical opportunities of sympathetic co-transmission in the control of human cardiovascular diseases will be highlighted.

Many diabetic men suffer from erectile dysfunction (ED). The etiology of diabetic impotence is complex, with neurogenic, vasculogenic, and disordered local neuroeffector regulatory mechanisms contributing to the pathology of ED. The introduction of oral phosphodiesterase-5 inhibitors has revolutionized medical therapy for ED. These drugs have become the primary initial treatment for ED, although the medications are less efficacious in diabetic than in nondiabetic patients. Treatment often relies on second-line therapies, including intracavernous injections of vasoactive substances and implantation of prosthetic devices. Recent work with animal models has advanced our knowledge of the molecular pathways involved in diabetic impotence, specifically the discovery of the adverse effects of advanced glycation end-products. Further work may elucidate chemopreventive strategies for the management of diabetic patients. This paper reviews the mechanisms and management of ED in patients with diabetes mellitus.

Synchronic flashing in fireflies is a precisely timed behavior. This is a potentially useful tool to study sensory processing, the location and circuitry of the flash oscillator, and neuroeffector processing and coupling. Synchronic flashing, once thought to occur only in Southeast Asian fireflies, has recently been shown to be a prominent part of the behavior of a North American Photinus and Photuris species. To gain insights into the mechanisms of synchronic timing in fireflies, we compared spontaneous flashing and entrainment flashing in Photuris frontalis LeConte, a synchronic firefly found in Georgia's Coastal Plain, to analogous flashing in Pteroptyx malaccae Olivier, a synchronic firefly found in Malaysia. The timing of spontaneously produced flashes and entrainment flashes was recorded by photometry. Artificially produced, rhythmic stimulus flashes were used to induce a counterfeit synchrony (between subject fireflies and an LED), i.e., flash entrainment. We found that the spontaneously produced interflash intervals were repeated with a high degree of precision in P. frontalis and P. malaccae. However, the pattern of flashing was different during spontaneous flashing and flash entrainment. An isolated P. frontalis flashed intermittently during spontaneously flashing and entrainment flashing. Flash entrainment in P. frontalis started with an initial inhibition and then steady-state entrainment occurred with a fixed delay. In contrast, an isolated P. malaccae flashed continuously during spontaneous flashing and entrainment flashing. No initial inhibition occurred at the start of entrainment, and there was a gradual change in interflash interval until steady-state entrainment occurred at a fixed delay. We think that in-depth studies of the flash activities of different synchronic firefly species, including the locally available P. frontalis, could help our understanding of rhythmic temporal coordination of behavior by the nervous system.

The detection of focal Ca(2+) transients (called neuroeffector Ca(2+) transients, or NCTs) in smooth muscle of the mouse isolated vas deferens has been used to detect the packeted release of ATP from nerve terminal varicosities acting at postjunctional P2X receptors. The present study investigates the sources and sequestration of Ca(2+) in NCTs. Smooth muscle cells in whole mouse deferens were loaded with the Ca(2+) indicator Oregon Green 488 BAPTA-1 AM and viewed with a confocal microscope. Ryanodine (10 microM) decreased the amplitude of NCTs by 45 +/- 6 %. Cyclopiazonic acid slowed the recovery of NCTs (from a time course of 200 +/- 10 ms to 800 +/- 100 ms). Caffeine (3 mM) induced spontaneous focal smooth muscle Ca(2+) transients (sparks). Neither of the T-type Ca(2+) channel blockers NiCl2 (50 microM) or mibefradil dihydrochloride (10 microM) affected the amplitude of excitatory junction potentials (2 +/- 5 % and -3 +/- 10 %) or NCTs (-20 +/- 36 % and 3 +/- 13 %). In about 20 % of cells, NCTs were associated with a local, subcellular twitch that remained in the presence of the alpha1-adrenoceptor antagonist prazosin (100 nM), showing that NCTs can initiate local contractions. Slow (5.8 +/- 0.4 microm s(-1)), spontaneous smooth muscle Ca(2+) waves were occasionally observed. Thus, Ca(2+) stores initially amplify and then sequester the Ca(2+) that enters through P2X receptors and there is no amplification by local voltage-gated Ca(2+) channels.

Objective : To estimate the sudomotor nerve conduction velocity (CV), the central processing time (CPT) and habituation of the skin conductance response (SCR). Methods : SCRs in response to a single deep inspiratory breath, an electrical stimulus and a sound click were obtained from the fingers and toes of 30 healthy adults. Sudomotor nerve conduction velocities were determined after measuring extremity length and latency differences. CPT was estimated by subtracting the efferent time and the known afferent times and neuroeffector times from the onset latency. Results : The inspiratory SCR habituated slower than the auditory or electrical SCRs. CVs of the 3 modalities did not differ statistically and their mean was 1.07 m s −1 (95% CI: 1.01–1.13). The inspiratory SCR arrived at the fingers 1.26±0.09 s after the onset of chest wall movement. Electrical and auditory SCR onset latencies at the fingers were 1.60±0.03 and 1.75±0.04 s, respectively. Their CPTs were 140 and 160 ms, estimated from the electrical and auditory SCR onset latencies to the fingers. The CPT for inspiratory SCR was estimated to occur during the inspiratory CPT after the inspiratory decision and before chest movement. Conclusions : In contrast to the SCR following an electrical or auditory stimulus, initiation of deep inspiratory SCR occurs before the inspiratory act, precluding any possible input from respiratory afferent receptors and implicating a central generator. Significance : This study provides new insights into the origin of the SCR following inspiration.

Summary 1 A variety of prostanoids were examined for their ability to alter the periarterial nerve stimulation-induced release of noradrenaline (NA) and neuropeptide Y immunoreactive compounds (NPY-ir) from the perfused mesenteric arterial bed of the rat. 2 Periarterial nerve stimulation (16 Hz) increased the overflow of NA, NPY-ir and perfusion pressure. 3 The prostacyclin (PGI2) analogues, carbaPGI2 and cicaprost both produced a concentration-dependent attenuation of the nerve stimulation-induced increase in NA, NPY-ir overflow and perfusion pressure. 4 The prostaglandin (PG) analogue PGE2 attenuated the evoked increase in NPY-ir overflow as well as a modest decrease in NA. 5 PGE1, sulprostone and iloprost attenuated the nerve stimulation-induced increase in NA overflow but not NPY-ir. 6 Neither PGF2α nor the thromboxane A2 analogue U46619 altered the evoked increase in NA or NPY-ir overflow. 7 The results support the view that sympathetic co-transmitter release can be differentially modulated by paracrine/autocrine mediators at sympathetic neuroeffector junctions.

The sympathetic nervous system regulates many different target tissues in the somatic and visceral domains of the body in a differentiated manner, indicating that there exist separate sympathetic pathways that are functionally defined by their target cells. Signals generated by central integration and channelled through the preganglionic neurons into the final sympathetic pathways are precisely transmitted through the para- and prevertebral ganglia and at the neuroeffector junctions to the effector cells. Neurophysiological recordings of activity in postganglionic neurons in skin and muscle nerves using microneurography in human subjects and in skin, muscle and visceral nerves, using conventional recording techniques in anaesthetized animals, clearly show that each type of sympathetic neuron exhibits a discharge pattern that is characteristic for its target cells and, therefore, its function. These findings justify labelling the neurons as muscle vasoconstrictor, cutaneous vasoconstrictor, sudomotor, lipomotor, cardiomotor, secretomotor neurons, etc. The discharge patterns monitor aspects of the central organization of the respective sympathetic system in the neuraxis and forebrain. They can be dissected into several distinct reflexes (initiated by peripheral and central afferent inputs) and reactions connected to central signals (related to respiration, circadian and other rhythms, command signals generated in the forebrain, etc). They are functional markers for the sympathetic final pathways. These neurophysiological recordings of the discharge patterns from functionally identified neurons of sympathetic pathways in the human and in animals are the ultimate reference for all experimental investigations that aim to unravel the central organization of the sympathetic systems. The similarities of the results obtained in the in vivo studies in the human and in animals justify concluding that the principles of the central organization of sympathetic systems are similar, if not identical, at least in the neuraxis, in both species. Future progress in the analysis of the central neuronal circuits that are associated with the different final sympathetic pathways will very much depend on whether we are able to align the human models and the animal models. Human models using microneurography have the advantage to work under awake conditions. The activity in the postganglionic neurons can be correlated with various other (afferent, centrally generated) signals, effector responses, perceptions, central changes monitored by imaging methods, etc. However, human models have considerable limitations. Animal models can be divided into in vivo models and various types of reduced in vitro models. Animal models allow using various methodological approaches (e.g., neurophysiological, pharmacological, modern anatomical tracing methods; behavioural animal models; transgenic animals), which cannot be used in the human. Interaction of the research performed in the human and animals will allow to design animal models that are relevant for diseases in which the sympathetic nervous systems is involved and to trace down the underlying pathophysiological mechanisms. The scientific questions to be asked are formulated on the basis of clinical observations resulting in testable hypotheses that are investigated in the in vivo human and animal models.