Sympathetic and Sensory-Motor Nerves in Peripheral Small Arteries.

Small arteries, which play important roles in controlling blood flow, blood pressure, and capillary pressure, are under nervous influence. Their innervation is predominantly sympathetic and sensory motor in nature, and while some arteries are densely innervated, others are only sparsely so. Innervation of small arteries is a key mechanism in regulating vascular resistance. In the second half of the previous century, the physiology and pharmacology of this innervation were very actively investigated. In the past 10-20 yr, the activity in this field was more limited. With this review we highlight what has been learned during recent years with respect to development of small arteries and their innervation, some aspects of excitation-release coupling, interaction between sympathetic and sensory-motor nerves, cross talk between endothelium and vascular nerves, and some aspects of their role in vascular inflammation and hypertension. We also highlight what remains to be investigated to further increase our understanding of this fundamental aspect of vascular physiology.

Role of NaV1.7 in postganglionic sympathetic nerve function in human and guinea-pig arteries.

NaV1.7 plays a crucial role in inducing and conducting action potentials in pain-transducing sensory nociceptor fibres, suggesting that NaV1.7 blockers could be effective non-opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt-PCR analysis revealed that 82% of sympathetic neurons isolated from guinea-pig stellate ganglia expressed NaV1.7 mRNA, with NaV1.3 being the only other tetrodotoxin-sensitive channel expressed in approximately 50% of neurons. We investigated the role of NaV1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective NaV1.7 inhibitors. Two highly selective NaV1.7 blockers, GNE8493 and PF 05089771, significantly inhibited postganglionic compound action potentials by approximately 70% (P < 0.01), with residual activity being blocked by the NaV1.3 inhibitor, ICA 121431. Electrical field stimulation (EFS) induced rapid contractions in guinea-pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the NaV1 blocker tetrodotoxin. Our results demonstrated that blocking NaV1.7 with GNE8493, PF 05089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea-pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting NaV1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways. KEY POINTS: 82% of sympathetic neurons isolated from the stellate ganglion predominantly express NaV1.7 mRNA. NaV1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves. NaV1.7 blockade substantially inhibits sympathetic nerve-mediated adrenergic contractions in human and guinea-pig blood vessels. Pharmacologically blocking NaV1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of NaV1.7 mutations on autonomic nerve activity.

Age-related decrease of cholinergic parasympathetic reflex vasodilation in the rat masseter muscle.

Skeletal muscle hemodynamics, including that in jaw muscles, is an important in their functions and is modulated by aging. Marked blood flow increases mediated by parasympathetic vasodilation may be important for blood flow in the masseter muscle (MBF); however, the relationship between parasympathetic vasodilation and aging is unclear. We examined the effect of aging on parasympathetic vasodilation evoked by trigeminal afferent inputs and their mechanisms by investigating the MBF during stimulation of the lingual nerve (LN) in young and old urethane-anesthetized and vago-sympathectomized rats. Electrical stimulation of the central cut end of the LN elicited intensity- and frequency-dependent increases in MBF in young rats, while these increases were significantly reduced in old rats. Increases in the MBF evoked by LN stimulation in the young rats were greatly reduced by hexamethonium and atropine administration. Increases in MBF in young rats were produced by exogenous acetylcholine in a dose-dependent manner, whereas acetylcholine did not influence the MBF in old rats. Significant levels of muscarinic acetylcholine receptor type 1 (MR1) and type 3 (MR3) mRNA were observed in the masseter muscle in young rats, but not in old rats. Our results indicate that cholinergic parasympathetic reflex vasodilation evoked by trigeminal afferent inputs to the masseter muscle is reduced by aging and that this reduction may be mediated by suppression of the expression of MR1 and MR3 in the masseter muscle with age.

Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats.

Nitric oxide (NO) has been shown to stimulate differentiation and increase the survival of ganglionic sympathetic neurons. The proportion of neuronal NOS-immunoreactive sympathetic preganglionic neurons is particularly high in newborn rats and decreases with maturation. However, the role of NO in the development of vascular sympathetic innervation has never been studied before. We tested the hypothesis that intrauterine NO deficiency weakened the development of vascular sympathetic innervation and thereby changed the contractility of peripheral arteries and blood pressure level in two-week-old offspring. Pregnant rats consumed NOS inhibitor L-NAME (250 mg/L in drinking water) from gestational day 10 until delivery. Pups in the L-NAME group had a reduced body weight and blood level of NO metabolites at 1-2 postnatal days. Saphenous arteries from two-week-old L-NAME offspring demonstrated a lower density of sympathetic innervation, a smaller inner diameter, reduced maximal active force and decreased α-actin/ß-actin mRNA expression ratio compared to the controls. Importantly, pups in the L-NAME group exhibited decreased blood pressure levels before, but not after, ganglionic blockade with chlorisondamine. In conclusion, intrauterine L-NAME exposure is followed by the impaired development of the sympathetic nervous system in early postnatal life, which is accompanied by the structural and functional remodeling of arterial blood vessels.

Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins.

BACKGROUND: The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied. METHODS: We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α-induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene Bmal1 (also known as Arntl) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process. RESULTS: In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type-specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of ß2-adrenergic receptor signaling. Loss of the core clock gene Bmal1 in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type-specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence. CONCLUSIONS: Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day-dependent vessel type-specific thrombotic events.

Sympathetic neural modulation of arterial stiffness in humans.

Elevated large-artery stiffness is recognized as an independent predictor of cardiovascular and all-cause mortality. The mechanisms responsible for such stiffening are incompletely understood. Several recent cross-sectional and acute experimental studies have examined whether sympathetic outflow, quantified by microneurographic measures of muscle sympathetic nerve activity (MSNA), can modulate large-artery stiffness in humans. A major methodological challenge of this research has been the capacity to evaluate the independent neural contribution without influencing the dynamic blood pressure dependence of arterial stiffness. The focus of this review is to summarize the evidence examining 1) the relationship between resting MSNA and large-artery stiffness, as determined by carotid-femoral pulse wave velocity or pulse wave reflection characteristics (i.e., augmentation index) in men and women; 2) the effects of acute sympathoexcitatory or sympathoinhibitory maneuvers on carotid-femoral pulse wave velocity and augmentation index; and 3) the influence of sustained increases or decreases in sympathetic neurotransmitter release or circulating catecholamines on large-artery stiffness. The present results highlight the growing evidence that the sympathetic nervous system is capable of modulating arterial stiffness independent of prevailing hemodynamics and vasomotor tone.

Muscle metaboreflex-induced increases in effective arterial elastance: effect of heart failure.

Dynamic exercise elicits robust increases in sympathetic activity in part due to muscle metaboreflex activation (MMA), a pressor response triggered by activation of skeletal muscle afferents. MMA during dynamic exercise increases arterial pressure by increasing cardiac output via increases in heart rate, ventricular contractility, and central blood volume mobilization. In heart failure, ventricular function is compromised, and MMA elicits peripheral vasoconstriction. Ventricular-vascular coupling reflects the efficiency of energy transfer from the left ventricle to the systemic circulation and is calculated as the ratio of effective arterial elastance (Ea) to left ventricular maximal elastance (Emax). The effect of MMA on Ea in normal subjects is unknown. Furthermore, whether muscle metaboreflex control of Ea is altered in heart failure has not been investigated. We utilized two previously published methods of evaluating Ea [end-systolic pressure/stroke volume (EaPV)] and [heart rate × vascular resistance (EaZ)] during rest, mild treadmill exercise, and MMA (induced via partial reductions in hindlimb blood flow imposed during exercise) in chronically instrumented conscious canines before and after induction of heart failure via rapid ventricular pacing. In healthy animals, MMA elicits significant increases in effective arterial elastance and stroke work that likely maintains ventricular-vascular coupling. In heart failure, Ea is high, and MMA-induced increases are exaggerated, which further exacerbates the already uncoupled ventricular-vascular relationship, which likely contributes to the impaired ability to raise stroke work and cardiac output during exercise in heart failure.

Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats.

Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha-nolamide (0.1-3.1 µg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 µg/kg NIDA41020, 100 µg/kg capsazepine, or 31 µg/kg cannabidiol; (ii) unaffected by 310 µg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 µg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB1, TRPV1 and probably GPR55, but not by CB2, receptors.

α-Adrenergic receptor regulation of skeletal muscle blood flow during exercise in heart failure patients with reduced ejection fraction.

Patients suffering from heart failure with reduced ejection fraction (HFrEF) experience impaired limb blood flow during exercise, which may be due to a disease-related increase in α-adrenergic receptor vasoconstriction. Thus, in eight patients with HFrEF (63 ± 4 yr) and eight well-matched controls (63 ± 2 yr), we examined changes in leg blood flow (Doppler ultrasound) during intra-arterial infusion of phenylephrine (PE; an α1-adrenergic receptor agonist) and phentolamine (Phen; a nonspecific α-adrenergic receptor antagonist) at rest and during dynamic single-leg knee-extensor exercise (0, 5, and 10 W). At rest, the PE-induced reduction in blood flow was significantly attenuated in patients with HFrEF (-15 ± 7%) compared with controls (-36 ± 5%). During exercise, the controls exhibited a blunted reduction in blood flow induced by PE (-12 ± 4, -10 ± 4, and -9 ± 2% at 0, 5, and 10 W, respectively) compared with rest, while the PE-induced change in blood flow was unchanged compared with rest in the HFrEF group (-8 ± 5, -10 ± 3, and -14 ± 3%, respectively). Phen administration increased leg blood flow to a greater extent in the HFrEF group at rest (+178 ± 34% vs. +114 ± 28%, HFrEF vs. control) and during exercise (36 ± 6, 37 ± 7, and 39 ± 6% vs. 13 ± 3, 14 ± 1, and 8 ± 3% at 0, 5, and 10 W, respectively, in HFrEF vs. control). Together, these findings imply that a HFrEF-related increase in α-adrenergic vasoconstriction restrains exercising skeletal muscle blood flow, potentially contributing to diminished exercise capacity in this population.

Why is the therapeutic effect of acute antimigraine drugs delayed? A review of controlled trials and hypotheses about the delay of effect.

In randomised controlled trials (RCTs) of oral drug treatment of migraine attacks, efficacy is evaluated after 2 hours. The effect of oral naratriptan 2.5 mg with a maximum blood concentration (Tmax ) at 2 hours increases from 2 to 4 hours in RCTs. To check whether such a delayed effect is also present for other oral antimigraine drugs, we hand-searched the literature for publications on RCTs reporting efficacy. Two triptans, 3 nonsteroidal anti-inflammatory drugs (NSAIDs), a triptan combined with an NSAID and a calcitonin gene-related peptide receptor antagonist were evaluated for their therapeutic gain with determination of time to maximum effect (Emax ). Emax was compared with known Tmax from pharmacokinetic studies to estimate the delay to pain-free. The delay in therapeutic gain varied from 1-2 hours for zolmitriptan 5 mg to 7 hours for naproxen 500 mg. An increase in effect from 2 to 4 hours was observed after eletriptan 40 mg, frovatriptan 2.5 mg and lasmiditan 200 mg, and after rizatriptan 10 mg (Tmax  = 1 h) from 1 to 2 hours. This strongly indicates a general delay of effect in oral antimigraine drugs. A review of 5 possible effects of triptans on the trigemino-vascular system did not yield a simple explanation for the delay. In addition, Emax for triptans probably depends partly on the rise in plasma levels and not only on its maximum. The most likely explanation for the delay in effect is that a complex antimigraine system with more than 1 site of action is involved.

A systematic review on persistent trigeminal artery, in searching for a therapeutic solution to idiopathic and unresponsive trigeminal nerve inflammations and migraines.

The rarely diagnosed persistent trigeminal artery (PTA) originates from the posterior bend or lateral wall of the intracavernous carotid artery and is the most common occurring type of remnant primitive fetal arteries. Even if PTA is uncommon, information and awareness about it could be of great help for clinicians dealing with cranial vascular imaging and operating this region. In addition, it could give a supporting response to the presence of a wide range of idiopathic and unresponsive disturbs that sometimes are erroneously interpreted and treated. There are very few published scientific reports of coexisting PTA and unilateral trigeminal neuralgia and migraine-cephalgia (MC). In this review we describe few reported and unreported cases regarding the manifestation of unresponsive trigeminal neuralgia and migraine due to the presence of PTA. Patients usually present with a clinical symptomatology with unstable blood hypertension, pain of typical trigeminal neuralgia and MC that cover unilaterally the occipital area over the second and third divisions of the nerve. The outbreaks may often become more severe during physical exertion, stress and hypertension. Angio-MRI may reveal the PTA with an occasional occurrence of parietal cavernoma. We also describe a case of chronic left MC case associated with an adjacent PTA close to the trigeminal nerve position. The size and location of the PTA was confirmed by a CT-Angiography. The MC was safely treated by bio-identical testosterone, human placenta extract (HPE), b-nicotinamide adenine dinucleotide (NADH) and low dose amlopidine. It is hypothesized that these types of primitive anastomose arteries that fully belong to the intracranial arterial vascular system do not perform any supportive functional activity. Nevertheless, they undergo the normal biological decay caused by the aging process and metabolic dysfunctions. Therefore, such primitive fetal arteries as PTA might be subjected not only to a faster structural deterioration but they would actively contribute to a series of mechanisms causing a variety of idiopathic intracranial vascular and structural symptoms. Consequently, this would change the primary therapeutic approach to solve this problem, today represented by surgical removal. Anatomic implications related to treatment procedure are also discussed.

Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity.

RATIONALE: Arterial endothelial cells are morphologically, functionally, and molecularly distinct from those found in veins and lymphatic vessels. How arterial fate is acquired during development and maintained in adult vessels is incompletely understood. OBJECTIVE: We set out to identify factors that promote arterial endothelial cell fate in vivo. METHODS AND RESULTS: We developed a functional assay, allowing us to monitor and manipulate arterial fate in vivo, using arteries isolated from quails that are grafted into the coelom of chick embryos. Endothelial cells migrate out from the grafted artery, and their colonization of host arteries and veins is quantified. Here we show that sympathetic innervation promotes arterial endothelial cell fate in vivo. Removal of sympathetic nerves decreases arterial fate and leads to colonization of veins, whereas exposure to sympathetic nerves or norepinephrine imposes arterial fate. Mechanistically, sympathetic nerves increase endothelial ERK (extracellular signal-regulated kinase) activity via adrenergic α1 and α2 receptors. CONCLUSIONS: These findings show that sympathetic innervation promotes arterial endothelial fate and may lead to novel approaches to improve arterialization in human disease.

Patterns of sural nerve innervation of the sural artery with implication for reconstructive surgery.

BACKGROUND: Most of the literature concerning the neurocutaneous flap is related to its anatomic investigation and clinical application, and the more in-depth physiological problem such as whether the cutaneous nerve contains sympathetic fibers that innervate its accompanying vessels has never been explored. MATERIALS AND METHODS: Dissection was first performed on three rabbits. In another 22 rabbits, two rabbits undergoing no surgery were used as the normal control group. In the remaining 20 rabbits, the 40 sides of hind limbs were divided into a nerve severance group, where the sural nerve was transected at its origin after creation of the proximally based sural neurocutaneous flap, and a nerve preservation group, in which the continuation of the sural nerve was preserved. The sural neurovascular bundles at four time points were harvested for immunohistochemical and Western blotting analyses of the expression of tyrosine hydroxylase (TH). An infrared thermal imager was used for measurement of the average flap temperature within the first 24 h. RESULTS: The sural neurovascular bundle entered the skin at 4.5 ± 1.2 cm above the lateral malleolus. The TH in the sural nerve and tunica adventitia of the sural artery showed a synchronized abated expression in the nerve severance group. The TH expression showed no decline in the nerve preservation group. The average flap temperature in the nerve severance group was higher than that in the nerve preservation group starting from 2 h after flap harvest (P = 0.05). CONCLUSIONS: The cutaneous nerve has meted out sympathetic fibers to the accompanying artery, regulating its vascular tone.

Differential Contribution of Nerve-Derived Noradrenaline to High K+-Induced Contraction Depending on Type of Artery.

High K+-induced contraction of arterial smooth muscle is thought to be mediated by membrane depolarization and subsequent activation of voltage-dependent Ca2+ channels (VDCCs). In line with this, this study found that contraction induced by 80 mM K+ was almost abolished by nifedipine (1 µM), a VDCC inhibitor, in isolated rat aorta, and was markedly suppressed in the iliac artery. However, nifedipine (1 µM) only partially suppressed high K+-induced contraction in the tail artery. The contractions remaining in the arteries were further reduced by non-selective cation channel (NSCC) inhibitors, including 2-aminoethoxydiphenyl borate (2-APB) (100 µM), SK&F96365 (10 µM), and 3,4-dihydro-6,7-dimethoxy-α-phenyl-N,N-bis[2-(2,3,4-trimethoxyphenyl)ethyl]-1-isoquinolineacetamide hydrochloride (LOE908) (10 µM). In particular, sustained tonic contraction was nearly abolished. Prazosin (0.3 µM), an α1-adrenoceptor antagonist, partially inhibited high K+-induced contraction in the tail and iliac arteries, but had no effect in the aorta. Consistently, tyramine potently induced contraction in the tail and iliac arteries, but not in the aorta. Furthermore, the inhibition by prazosin and NSCC inhibitors of the high K+-induced contraction in the presence of nifedipine was comparable. These results suggest that depending on the type of artery, high K+-induced contraction is mediated by Ca2+ influx not only through VDCCs but also through NSCCs, the activation of which is due to the activation of α1-adrenoceptors by the released noradrenaline from sympathetic nerve terminals resulting from high K+ stimulation.

Locus coeruleus noradrenergic innervation of the amygdala facilitates alerting-induced constriction of the rat tail artery.

The amygdala, innervated by the noradrenergic locus coeruleus, processes salient environmental events. α2-adrenoceptor-stimulating drugs (clonidine-like agents) suppress the behavioral and physiological components of the response to salient events. Activation of sympathetic outflow to the cutaneous vascular bed is part of the physiological response to salience-mediated activation of the amygdala. We have determined whether acute systemic and intra-amygdala administration of clonidine, and chronic immunotoxin-mediated destruction of the noradrenergic innervation of the amygdala, impairs salience-related vasoconstrictor episodes in the tail artery of conscious freely moving Sprague-Dawley rats. After acute intraperitoneal injection of clonidine (10, 50, and 100 µg/kg), there was a dose-related decrease in the reduction in tail blood flow elicited by alerting stimuli, an effect prevented by prior administration of the α2-adrenergic blocking drug idazoxan (1 mg/kg ip or 75 nmol bilateral intra-amygdala). A dose-related decrease in alerting-induced tail artery vasoconstriction was also observed after bilateral intra-amygdala injection of clonidine (5, 10, and 20 nmol in 200 nl), an effect substantially prevented by prior bilateral intra-amygdala injection of idazoxan. Intra-amygdala injection of idazoxan by itself did not alter tail artery vasoconstriction elicited by alerting stimuli. Intra-amygdala injection of saporin coupled to antibodies to dopamine-ß-hydroxylase (immunotoxin) destroyed the noradrenergic innervation of the amygdala and the parent noradrenergic neurons in the locus coeruleus. The reduction in tail blood flow elicited by standardized alerting stimuli was substantially reduced in immunotoxin-treated rats. Thus, inhibiting the release of noradrenaline within the amygdala reduces activation of the sympathetic outflow to the vascular beds elicited by salient events.

Digital periarterial sympathectomy in the management of post-traumatic Raynaud syndrome.

OBJECTIVE: Among Basque handball players, the repeated impact of a ball on the palms of their hands hundreds of thousands of times throughout their sporting careers produces Raynaud syndrome. Treating this patient group is complex. Our objective was to assess the efficacy of digital periarterial sympathectomy in this patient group. METHODS: The study included all of the federated amateur and professional Basque handball patients who presented with Raynaud syndrome assessed in the vascular surgery service between January 2005 and December 2012. The postoperative assessment included a physical examination, basal photoplethysmography and photoplethysmography after heat hyperemia, and arteriography or magnetic resonance angiography. RESULTS: All 182 digital periarterial sympathectomies in the 114 fingers of 60 patients were in Porter functional class III or IV. All patients were discharged within the first 48 hours. Follow-up results, with a mean of 2 years ± 5 months, were 100%. All patients presented immediate pain remission, recovery of comfort, normal nail growth, rapid healing of all ulcers, distal anhidrosis, and return to active sport participation. The results remain steady in 58 patients (93.5%). Mean time until return to sports activity was 9.95 ± 1.61 weeks. CONCLUSIONS: Digital periarterial sympathectomy is a simple, relatively nonaggressive technique without adverse side effects and with excellent medium-term results. In patients with Raynaud syndrome refractory to medical treatment and with threat to the viability of one or several fingers, digital periarterial sympathectomy can be the first treatment option, especially in cases of arteritis associated with very severe spasms.

Abnormal Origin and Course of the Accessory Phrenic Nerve: Case Report.

In the current cadaveric study an unusual sizeable accessory phrenic nerve (APN) was encountered emerging from the trunk of the supraclavicular nerves and forming a triangular loop that was anastomosing with the phrenic nerve. That neural loop surrounded the superficial cervical artery which displayed a spiral course. The form of a triangular loop of APN involving the aforementioned artery and originating from the supraclavicular nerve to the best of our knowledge has not been documented previously in the literature. The variable morphological features of the APN along with its clinical applications are briefly discussed.

Origins of variation in conducted vasomotor responses.

Regulation of blood flow in the microcirculation depends on synchronized vasomotor responses. The vascular conducted response is a synchronous dilatation or constriction, elicited by a local electrical event that spreads along the vessel wall. Despite the underlying electrical nature, however, the efficacy of conducted responses varies significantly between different initiating stimuli within the same vascular bed as well as between different vascular beds following the same stimulus. The differences have stimulated proposals of different mechanisms to account for the experimentally observed variation. Using a computational approach that allows for introduction of structural and electrophysiological heterogeneity, we systematically tested variations in both arteriolar electrophysiology and modes of stimuli. Within the same vessel, our simulations show that conduction efficacy is influenced by the type of cell being stimulated and, in case of depolarization, by the stimulation strength. Particularly, simultaneous stimulation of both endothelial and vascular smooth muscle cells augments conduction. Between vessels, the specific electrophysiology determines membrane resistance and conduction efficiency-notably depolarization or radial currents reduce electrical spread. Random cell-cell variation, ubiquitous in biological systems, only cause small or no reduction in conduction efficiency. Collectively, our simulations can explain why CVRs from hyperpolarizing stimuli tend to conduct longer than CVRs from depolarizing stimuli and why agonists like acetylcholine induce CVRs that tend to conduct longer than electrical injections. The findings demonstrate that although substantial heterogeneity is observed in conducted responses, it can be largely ascribed to the origin of electrical stimulus combined with the specific electrophysiological properties of the arteriole. We conclude by outlining a set of "principles of electrical conduction" in the microcirculation.

Neural control of circulation and exercise: a translational approach disclosing interactions between central command, arterial baroreflex, and muscle metaboreflex.

The last 100 years witnessed a rapid and progressive development of the body of knowledge concerning the neural control of the cardiovascular system in health and disease. The understanding of the complexity and the relevance of the neuroregulatory system continues to evolve and as a result raises new questions. The purpose of this review is to articulate results from studies involving experimental models in animals as well as in humans concerning the interaction between the neural mechanisms mediating the hemodynamic responses during exercise. The review describes the arterial baroreflex, the pivotal mechanism controlling mean arterial blood pressure and its fluctuations along with the two main activation mechanisms to exercise: central command (parallel activation of central somatomotor and autonomic descending pathways) and the muscle metaboreflex, the metabolic component of exercise pressor reflex (feedback from ergoreceptors within contracting skeletal muscles). In addition, the role of the cardiopulmonary baroreceptors in modulating the resetting of arterial baroreflex is identified, and the mechanisms in the central nervous system involved with the resetting of baroreflex function during dynamic exercise are also described. Approaching a very relevant clinical condition, the review also presents the concept that the impaired arterial baroreflex function is an integral component of the metaboreflex-mediated exaggerated sympathetic tone in subjects with heart failure. This increased sympathetic activity has a major role in causing the depressed ventricular function observed during submaximal dynamic exercise in these patients. The potential contribution of a metaboreflex arising from respiratory muscles is also considered.

Limb suction evoked during arterial occlusion causes systemic sympathetic activity in humans.

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP). We hypothesized that the application of suction to the human limbs would activate this venous distension reflex and raise sympathetic outflow. We placed airtight pressure tanks and applied 100 mmHg negative pressure to an arterially occluded limb (occlusion and suction, O&S) to induce tissue deformation without fluid translocation. BP, heart rate (HR), and MSNA were assessed in 19 healthy subjects during 2 min of arm or leg O&S. Occlusion without suction served as a control. During a separate visit, saline (5% forearm volume) was infused into veins of the arterially occluded arm (n = 13). The O&S increased limb circumference, MSNA burst rate (arm: Δ6.7 ± 0.7; leg: Δ6.8 ± 0.7 bursts/min), and total activity (arm: Δ199 ± 14; leg: Δ172 ± 22 units/min) and BP (arm: Δ4.3 ± 0.3; leg: Δ9.4 ± 1.4 mmHg) from the baseline. The MSNA and BP responses during arm O&S correlated with those during leg O&S. Occlusion alone had no effect on MSNA and BP. MSNA (r = 0.607) responses during arm O&S correlated with those evoked by the saline infusion into the arm. These correlations suggest that sympathetic activation during limb O&S is likely, at least partially, to be evoked via the venous distension reflex. These data suggest that suction of an occluded limb evokes sympathetic activation and that the limb venous distension reflex exists in arms and legs of normal humans.