Neuroeffector Mechanisms Research Articles

Robert Furchgott (1916-2009): A scientist with a mission.

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.

Effect of inhalation exposure to wheat flour on sputum levels of brain-derived neurotrophic factor

In the physiopathogenesis of occupational asthma (OA), neurogenic mechanisms may be involved, although they remain poorly understood. Currently, there is increasing interest in the potential role of neuroeffector mechanisms in asthma. The neurotrophins family, comprising nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin 3, and neurotrophin 4, appears to have a role in features of asthma, including airway hyperresponsiveness and inflammation, neuronal plasticity, and airway remodelling.

The nerve fiber relationship with human arrector pili muscle cells : electron microscopy findings

Introduction. The arrector pili muscle has been the topic of several morphological studies for the different modality of association with the follicural unit, belonging to different body region ,employing reconstructed tridimensional images of serial histological sections. However up to date no ultrastructural study on the nerve fibers and their relationship with smooth muscle cells of the human muscle has been carried out.This is a very important issue to understand the anatomical bases supporting the neuroeffector mechanism modulating piloerection in normal and pathological condition. Materials and methods. Arm skin biopsies from children suspected for metabolic diseases but resulted negative to previous microscope observation, were reexamined for the presence of arrector pili smooth muscle cells under a transmission electron microscopy.(Philips,CM10). Results. The smooth muscle cells appear in a more or less narrow relationship with axonal varicosities of unmyelinated nerve fibers localized near muscle plasmalemma . At neuromuscular region the Schwann envelope appears partially or totally retracted from axonal varicosities and a variable intercellular gap (0,15-0,3 um) remained between axonal and plasmalemmal membrane. The plasmalemma shows irregular profile with frequently protruded tract ,with towards the axon.The axon contained vesicles different for diameter and content : large dense core vesicles ,small dense core, and clear vesicles. Conclusion. The ultrastructural morphology of arrector pili muscle myoneural junction ,appears quite different from that of the skin epithelial and myoneural junctions ,according to the neuroeffector mechanism modulating piloerection.

Sex, hormones and neuroeffector mechanisms.

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 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. Although involvement of central serotonergic centres 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.

New perspectives on vascular wall signaling: role of perivascular adipocytes and fibroblasts.

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.

Impaired Autonomic Regulation of Resistance Arteries in Mice With Low Vascular Endothelial Growth Factor or Upon Vascular Endothelial Growth Factor Trap Delivery

Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. Here, we report that VEGF( partial differential/ partial differential) mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. These findings uncover a novel role for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients.

Interstitial cells of Cajal in diabetic gastroenteropathy

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.

Differences in sympathetic neuroeffector transmission to rat mesenteric arteries and veins as probed by in vitro continuous amperometry and video imaging

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 microm), reduced constrictions in MA but not in MV while the alpha(1)-adrenergic receptor antagonist, prazosin (0.1 microm), blocked constrictions in MV but not in MA; (iv) NA overflow for MA was enhanced by the alpha(2)-adrenergic receptor antagonist, yohimbine (1.0 microm), and attenuated by the alpha(2)-adrenergic receptor agonist, UK 14,304 (1.0 microm), while yohimbine and UK 14,304 had little effect in MV; (v) cocaine (10 microm) 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.

Renal Sympathetic Neuroeffector Function in Renovascular and Angiotensin II–Dependent Hypertension in Rabbits

We tested the hypotheses that the gains of specific renal sympathetic neuroeffector mechanisms are altered in secondary hypertension and that the nature of these alterations depends on the precise experimental setting of the kidney. Rabbits were sham operated, or made comparably hypertensive (mean arterial pressure increased 17% to 24%) by clipping the left or right renal artery or by chronic infusion of angiotensin II (20 to 50 ng kg(-1) min(-1) SC). Four to 6 weeks later, under pentobarbital anesthesia, the left renal nerves were sectioned and electrically stimulated at low (0 to 2 Hz) and high (4 to 8 Hz) frequencies. Neurally evoked reductions in total renal blood flow, cortical perfusion, urine flow, and sodium excretion and increases in renal norepinephrine spillover were not significantly greater in kidneys of hypertensive rabbits than normotensive controls. Neurally evoked increases in renal renin release and the slope of the relationship between renin release and norepinephrine spillover were less in kidneys of hypertensive rabbits than normotensive controls. Low-frequency renal nerve stimulation reduced medullary perfusion, which was negatively correlated with renal norepinephrine spillover in kidneys from all 3 groups of hypertensive rabbits but not normotensive controls. Two-hertz stimulation reduced medullary perfusion by 19% in hypertensive rabbits but not in normotensive rabbits. Thus, of all of the renal sympathetic neuroeffector mechanisms studied, only neural control of medullary perfusion was enhanced in these models of secondary hypertension. This effect appears to be mediated postjunctionally, not through enhanced neural norepinephrine release, and may contribute to the development and/or maintenance of hypertension in these models.

Fundamentals of Neurogastroenterology: Basic Science

The focus of neurogastroenterology in Rome II was the enteric nervous system (ENS). To avoid duplication with Rome II, only advances in ENS neurobiology after Rome II are reviewed together with stronger emphasis on interactions of the brain, spinal cord, and the gut in terms of relevance for abdominal pain and disordered gastrointestinal function. A committee with expertise in selective aspects of neurogastroenterology was invited to evaluate the literature and provide a consensus overview of the Fundamentals of Neurogastroenterology textbook as they relate to functional gastrointestinal disorders (FGIDs). This review is an abbreviated version of a fuller account that appears in the forthcoming book, Rome III. This report reviews current basic science understanding of visceral sensation and its modulation by inflammation and stress and advances in the neurophysiology of the ENS. Many of the concepts are derived from animal studies in which the physiologic mechanisms underlying visceral sensitivity and neural control of motility, secretion, and blood flow are examined. Impact of inflammation and stress in experimental models relative to FGIDs is reviewed as is human brain imaging, which provides a means for translating basic science to understanding FGID symptoms. Investigative evidence and emerging concepts implicate dysfunction in the nervous system as a significant factor underlying patient symptoms in FGIDs. Continued focus on neurogastroenterologic factors that underlie the development of symptoms will lead to mechanistic understanding that is expected to directly benefit the large contingent of patients and care-givers who deal with FGIDs.

Does arterial myogenic tone determine blood flow distribution in vivo?

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

3 Developmental Contractile Response in the Chicken Embryo Ductus Arteriosus in Vitro

Background and aim: During prenatal life the chicken embryo presents a pattern of circulation similar to mammalians. Despite the abundant information about ontogeny of vascular reactivity in mammalian ductus arteriosus (DA), this has not been characterized in the chicken embryo. The aim of the present work was to study the response to vasoconstrictors of the chicken embryo DA between 0.7 and 0.9 incubation. Methods: Isolated right DA segments from chick embryos at day 15 and day 19 of the 21-d incubation were mounted in a myograph for isometric tension recording, bubbled with 0%, 5% or 95% O2/5% CO2. The contractile responses induced by KCl (31.25 mM-125 mM), the thromboxane A2 mimetic U46619 (10 nM-0.1 microM), endothelin-1 (ET-1, 10 nM- 10 microM), and the adrenergic agonist noradrenaline (NA, 0.3 nM- 10 mM) were tested. Response to oxygen was tested in a separate protocol. Sympathetic neuroeffector mechanisms were studied using electrical field stimulation (EFS, 0.25 16 Hz, 2 ms, 85 mA). Density of sympathetic innervation was evaluated using glyoxylic acid staining. Results: Chicken embryo DA responded to depolarizing high-K+ solution with a tonic contraction that increased with age. Also the contractile responses to NA, U46619 and ET-1 augmented. Depletion of calcium abolished the contractile response to K+ and NA, whereas the response to ET-1 decreased 77% and to U46619 decreased 20%. EFS did not evoke any response and catecholamine-containing perivascular nerves were not observed at any age. No clear response to oxygen in either 15 or 19 days embryos was observed. A contractile response to oxygen was only observed in 21 days externally pipped embryos. Conclusions: The DA of the chicken embryo responded, in vitro, to receptor-dependent and -independent contraction. The responses to contractile agonists augmented with age. The response to oxygen was only present at a very late stage of incubation.

Sympathetic responses to stress and rilmenidine in 2K1C rabbits: evidence of enhanced nonvascular effector mechanism.

We determined whether the sympathetic excitatory responses to environmental stressors and the sympathoinhibitory responses to rilmenidine are altered by renovascular hypertension. Rabbits were made hypertensive with a clip on the right renal artery, and a left renal nerve recording electrode was implanted. After 3 or 6 weeks, the animals were given air-jet stress and loud noise stress before and after intravenous rilmenidine. Three and 6 weeks after renal clipping, mean arterial pressure was 28% and 36% greater than preclip values. Air-jet stress elicited a marked increase in renal sympathetic nerve activity, mean arterial pressure, and heart rate. Renal sympathetic nerve activity responses were much greater in hypertensive rabbits, but the pressor responses were similar to those observed in normotensive animals. Acute administration of rilmenidine decreased blood pressure more in hypertensive animals but with a much lesser inhibition of sympathetic activity. Rilmenidine markedly reduced increased sympathetic activity during air-jet stress in 3-week clipped rabbits but to a lesser extent in the other groups. These studies show that while sympathetic responses to stress were markedly enhanced in renal clip hypertensive rabbits, they did not result in greater pressor responses, thus suggesting that vascular neuroeffector mechanisms were not altered. By contrast, the increased effects of rilmenidine suggest a much greater contribution to the hypertension by the sympathetic nervous system, but one that is caused by an enhanced "nonvascular" neuroeffector mechanism. As such, sympathoinhibitory agents such as rilmenidine are very suitable and very effective agents for the treatment of renovascular hypertension.

Neuroeffector mechanisms involved in the regulation of dog splenic arterial tone.

It has been recognized that sympathetic neurons release several transmitters but mainly adenosine 5'-triphosphate (ATP), noradrenaline, and neuropeptide Y (NPY). Recently, we reported that periarterial nerve electrical stimulation (PNS) produced biphasic vasoconstrictions consisting of an initial transient, predominantly P2X-purinoceptor-mediated constriction followed by a prolonged, alpha(1)-adrenoceptor-mediated one in canine isolated splenic arteries. In this article, we tried to analyze the effects of several selective key drugs that influence the PNS-induced responses, and we functionally showed sympathetic transmitter releasing mechanisms by pharmacological analysis using purinergic, adrenergic, and NPYergic agonists and antagonists.

Neuroeffector Mechanisms Involved in the Regulation of Dog Splenic Arterial Tone

Neuroeffector Mechanisms Involved in the Regulation of Dog Splenic Arterial Tone

Cholinergic innervation of pial arteries in senescent rats: an immunohistochemical study

Perivascular acetylcholine (ACh)-immunoreactive nerve fibres were demonstrated in basilar and middle cerebral arteries, in pial arteries and arterioles and in intracerebral arteries of male Fisher 344 rats of 6 months (young), 15 months (adult) and 22 months (senescent). Analysis included whole mounts of basilar and middle cerebral arteries, of pial arteries and sections of brain including pia-arachnoid membrane to demonstrate the localization of nerve fibres throughout the wall of pial and of intracerebral arteries. ACh-immunoreactive nerve fibres were demonstrated by indirect immunohistochemistry using a polyclonal anti-ACh antibody and their relative density was quantified. Perivascular ACh-immunoreactive nerve fibres were located in basilar and middle cerebral arteries, in pial arteries and arterioles and in intracerebral arteries. These fibres were found in the adventitia and adventitia–media border with a higher density in pial rather than in intracerebral arteries. A decrease of ACh-immunoreactive nerve fibres was observed both in pial and intracerebral arteries of adult or senescent rats compared to younger cohorts. The direct demonstration of ACh-immunoreactive nerve fibres in the cerebrovascular tree may contribute to evaluate the influence of experimental and pathological conditions on cerebrovascular cholinergic neuroeffector mechanisms, including a role of cholinergic innervation in the pathophysiology of cerebrovascular disease of the elderly.

Longchain n−3 polyunsaturated fatty acids and blood vessel function

The cardiovascular health benefits of longchain n-3 polyunsaturated fatty acids (PUFAs) have been reported to exert at several different cellular control mechanisms. These include, effects on lipoprotein metabolism, haemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms. The majority of such cardiovascular benefits of n-3 PUFAs are likely to be mediated in the vascular wall and at the vascular endothelium level, since this monolayer of cells plays a central role in the regulation and maintenance of cardiovascular homeostasis and function. While these processes include endothelium-derived vasorelaxant and vasoconstrictor compounds, the vascular endothelium also plays host to many receptors, binding proteins, transporters and signalling mechanisms. Accordingly, endothelial dysfunction, which underlies many cardiovascular disease conditions, can trigger acute vascular events including vasospasm, thrombosis or restenosis leading to ischaemia. The longchain n-3 PUFAs have been reported to possess several properties that may positively influence vascular function. These include favourable mediator profiles (nitric oxide, eicosanoids) that influence vascular reactivity, change in vascular tone via actions on selective ion channels, and maintenance of vascular integrity. In addition to direct effects on contractility, n-3 PUFAs may affect vascular function, and the process of atherogenesis, via inhibition of vascular smooth muscle cell proliferation at the gene expression level, and by modifying expression of inflammatory cytokinesis and adhesion molecules. Collectively, these properties are consistent with pleiotropic actions of longchain n-3 PUFAs, and may explain the beneficial cardiovascular protection of this family of fatty acids that have been clearly evident through epidemiological data as well from more recent large-scale clinical trials.

The role of neuroeffector mechanisms in the pathogenesis of asthma

Neural regulation of the airways consists of cholinergic excitatory, adrenergic inhibitory nerves and nonadrenergic, noncholinergic (NANC) nerves. NANC nerves can be either inhibitory or excitatory. Cholinergic nerves form the predominant bronchoconstrictor neural pathway in human airways. Acetylcholine controls neuronal and nonneuronal target cells via a short-lived action at nicotinic and muscarinic receptors. The most important control over acetylcholine release from postganglionic cholinergic nerves is exerted by acetylcholine itself. The M2 autoreceptor is located prejunctionally on postganglionic nerves. Its stimulation limits the further release of acetylcholine. A loss of function in the neuronal muscarinic M2 autoreceptor occurs after exposure to allergen, ozone, or viruses. In human airways, inhibitory NANC (i-NANC) mechanisms are the only neural bronchodilatory mechanisms. The presumed neurotransmitters of the i-NANC system are vasoactive intestinal peptide and nitric oxide. Substance P and neurokinin A have been implicated as the neurotransmitters mediating the excitatory part of the NANC nervous system. NK2 receptors are present on smooth muscle of both large and small airways and mediate part of the bronchoconstrictor effect of tachykinins. Most of the proinflammatory effects of substance P are mediated by the NK1 receptor. Tachykinin receptor antagonists are currently being developed as a possible anti-asthma treatment. An extensive cross-talk exists between nerves and the immune system. The complexity of the picture has increased further as it has become clear that classical neurotransmitters, such as acetylcholine and neuropeptides, are produced by nonneuronal cells.

Absence of Endothelium in Invertebrate Blood Vessels: Significance of Endothelium and Sympathetic Nerve/Medial Smooth Muscle in the Vertebrate Vascular System

In the course of evolution, two remarkable changes seem to have occurred in vertebrate circulation: the appearance and development of the “endothelium or endothelial tubular system” and “sympathetic nerve/medial smooth muscle system”. In the present article, some relevant literature is reviewed and discussed. Absence of endothelium in the vascular wall of most invertebrates had been known and was confirmed by recent electron microscopic studies. The medial smooth muscle is rather proper to vertebrate vessels. It seems to have appeared after emergence of and in association with the endothelial tubular system. Phylogenetically, the parasympathetic nervous system is thought to be older than the sympathetic system. The former is distributed to viscera and the latter developed in close relation with the vascular system. It is assumed that during evolution, a circulatory system composed of the heart and endothelial tubular system first formed in vertebrates, medial smooth muscle then appeared for regulation of the system, and innervation of the muscle tissue took place. This sequence of development assumed for phylogenesis is actually realized in the ontogenetic processes. We thus propose a hypothesis that the “sympathetic nerve /medial smooth muscle system” may be regarded as a new neuroeffector mechanism that developed for systemic regulation of the endothelium-lined closed vascular system in vertebrates. A few implications of the hypothesis are presented.

Cardiac vagal responsiveness during development in spontaneously hypertensive rats

In the present study we sought to determine the effect of age, hypertension and endogenous angiotensin on the chronotropic responses to vagal stimulation in urethane anesthetized-normotensive Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR). After β-adrenoceptor blockade with atenolol, the right and left vagal nerves were stimulated with graded frequencies between 1 and 32 Hz in 5-, 8- and 22-week-old animals. At all ages and in both strains, there was a strong linear relationship between the degree of bradycardia and the log of the stimulation frequency. At the age of 5 weeks, the bradycardia to stimulation of the right vagus was greater in SHR than that observed in WKY ( P<0.05). However, in 8- and 22 week-old animals, no differences were observed between the response to vagal stimulation in WKY and SHR. Thus, there was an age-dependent increase in the response to right vagal stimulation in WKY, but no such trend in SHR. No significant age-dependent changes in left vagal responses were observed in either strain. Left vagal responses were approximately half of the response to right vagal stimulation at all ages in SHR and in 8–22 week WKY, but similar to right vagal responses in 5 week WKY. Administration of the angiotensin converting enzyme inhibitor perindopril, which effectively blocked the formation of endogenous angiotensin, did not affect responses to vagal stimulation at any age, in either strain. These results suggest that the baroreflex vagal deficit observed in adult SHR compared to WKY is not due to a difference in the responsiveness of the cardiac vagal neuroeffector mechanism nor due to an effect of circulating angiotensin II. Furthermore, the enhanced vagal bradycardia observed in very young SHR which was due primarily to the earlier establishment of the adult vagal response pattern may indicate accelerated vagal development in this strain compared to WKY.