Direct Sympathetic Innervation Research Articles

PlcE Activity is Essential For PACAP-Stimulated Secretion from Chromaffin Cells

The adrenal medulla is an important branch of the sympathetic nervous system. Chromaffin cells, which serve as the secretory units of the medulla, receive direct sympathetic innervation via the splanchnic nerves. Secretion from the medulla is primarily caused by two neurotransmitters - acetylcholine (ACh) and pituitary adenylate cyclase activating polypeptide (PACAP) - released from splanchnic nerve terminals. ACh-stimulated secretion is associated with basal sympathetic tone; on the other hand, secretion stimulated by PACAP is associated with heightened sympathetic tone and the fight-or-flight response.

β2-Adrenergic Signaling Modulates Mitochondrial Function and Morphology in Skeletal Muscle in Response to Aerobic Exercise.

The molecular mechanisms underlying skeletal muscle mitochondrial adaptations induced by aerobic exercise (AE) are not fully understood. We have previously shown that AE induces mitochondrial adaptations in cardiac muscle, mediated by sympathetic stimulation. Since direct sympathetic innervation of neuromuscular junctions influences skeletal muscle homeostasis, we tested the hypothesis that β2-adrenergic receptor (β2-AR)-mediated sympathetic activation induces mitochondrial adaptations to AE in skeletal muscle. Male FVB mice were subjected to a single bout of AE on a treadmill (80% Vmax, 60 min) under β2-AR blockade with ICI 118,551 (ICI) or vehicle, and parameters of mitochondrial function and morphology/dynamics were evaluated. An acute bout of AE significantly increased maximal mitochondrial respiration in tibialis anterior (TA) isolated fiber bundles, which was prevented by β2-AR blockade. This increased mitochondrial function after AE was accompanied by a change in mitochondrial morphology towards fusion, associated with increased Mfn1 protein expression and activity. β2-AR blockade fully prevented the increase in Mfn1 activity and reduced mitochondrial elongation. To determine the mechanisms involved in mitochondrial modulation by β2-AR activation in skeletal muscle during AE, we used C2C12 myotubes, treated with the non-selective β-AR agonist isoproterenol (ISO) in the presence of the specific β2-AR antagonist ICI or during protein kinase A (PKA) and Gαi protein blockade. Our in vitro data show that β-AR activation significantly increases mitochondrial respiration in myotubes, and this response was dependent on β2-AR activation through a Gαs-PKA signaling cascade. In conclusion, we provide evidence for AE-induced β2-AR activation as a major mechanism leading to alterations in mitochondria function and morphology/dynamics. β2-AR signaling is thus a key-signaling pathway that contributes to skeletal muscle plasticity in response to exercise.

Cardiorespiratory interactions in the Pacific spiny dogfish, Squalus suckleyi.

Elasmobranchs are a group of cartilaginous fish with no direct sympathetic innervation of the heart or gills. Fast cardiorespiratory regulation is controlled solely by the parasympathetic branch of the autonomic nervous system. Cardiovascular changes associated with ventilation are commonly present in the form of respiratory sinus arrhythmia (RSA) and as cardiorespiratory synchrony (CRS, in which there is a 1:1 beat to breath ratio). The latter has been hypothesized to maximize oxygen uptake, coupling the pulsatile flows of blood and water in the gills. Given this, we hypothesized that CRS should be more prevalent in situations of low oxygen supply and RSA should be abolished by vagotomy. To test this, we investigated the role of the vagus nerve in mediating cardiorespiratory responses to changing environmental oxygen conditions in the elasmobranch Squalus suckleyi Hypoxia and hyperoxia had little effect on heart rate but did alter breathing frequency and amplitude. Atropine yielded an overall tachycardia in all oxygen conditions and abolished all heart rate variability (HRV), suggesting that HRV solely reflects fluctuating vagal tonus on the heart. Regardless of the presence of atropine, hypoxia still induced an increase in ventilation rate and depth. CRS was only found during progressive hyperoxia post-atropine, when heart rate was uninhibited and ventilation was slowed owing to the increase in oxygen supply, suggesting that in S. suckleyi, CRS is an epiphenomenon and not actively regulated to maximize gas exchange efficiency.

Loss of Sympathetic Nerves in Spleens from Patients with End Stage Sepsis.

The spleen is an important site for central regulation of immune function by noradrenergic sympathetic nerves, but little is known about this major region of neuroimmune communication in humans. Experimental studies using animal models have established that sympathetic innervation of the spleen is essential for cholinergic anti-inflammatory responses evoked by vagal nerve stimulation, and clinical studies are evaluating this approach for treating inflammatory diseases. Most data on sympathetic nerves in spleen derive from rodent studies, and this work has established that remodeling of sympathetic innervation can occur during inflammation. However, little is known about the effects of sepsis on spleen innervation. Our primary goals were to (i) localize noradrenergic nerves in human spleen by immunohistochemistry for tyrosine hydroxylase (TH), a specific noradrenergic marker, (ii) determine if nerves occur in close apposition to leukocytes, and (iii) determine if splenic sympathetic innervation is altered in patients who died from end stage sepsis. Staining for vesicular acetylcholine transporter (VAChT) was done to screen for cholinergic nerves. Archived paraffin tissue blocks were used. Control samples were obtained from trauma patients or patients who died after hemorrhagic stroke. TH + nerves were associated with arteries and arterioles in all control spleens, occurring in bundles or as nerve fibers. Individual TH + nerve fibers entered the perivascular region where some appeared in close apposition to leukocytes. In marked contrast, spleens from half of the septic patients lacked TH + nerves fibers and the average abundance of TH + nerves for the septic group was only 16% of that for the control group (control: 0.272 ± 0.060% area, n = 6; sepsis: 0.043 ± 0.026% area, n = 8; P < 0.005). All spleens lacked cholinergic innervation. Our results provide definitive evidence for the distribution of noradrenergic nerves in normal human spleen and the first evidence for direct sympathetic innervation of leukocytes in human spleen. We also provide the first evidence for marked loss of noradrenergic nerves in patients who died from sepsis. Such nerve loss could impair neuroimmunomodulation and may not be limited to the spleen.

Sympathetic nerves regulate rhythmic leukocyte recruitment to arteries and veins

Recent evidence points to a critical role of the time‐of‐day in the regulation of leukocyte recruitment to tissues. Using in vivo quantitative imaging analyses across the day in inflammatory scenarios, we observed circadian (~24h) leukocyte recruitment in arteries and veins of the macro‐ and microvasculature. Interestingly however, while in arteries the number of adherent cells peaked in the morning, in veins it peaked at night. These differences were functionally associated with a vessel‐type‐specific oscillatory pattern in the expression of the adhesion molecule ICAM‐1 but not of other promigratory molecules or clock genes. ICAM‐1‐deficient mice lacked rhythmic leukocyte adhesion in both arteries and veins, which was also observed in studies using functional ICAM‐1‐blocking antibodies. Since the sympathetic nervous system (SNS) is an important orchestrator of rhythmicity in peripheral tissues, we disrupted the SNS systemically by 6‐OHDA treatment. This resulted in a lack of oscillations in both arteries and veins. To assess the functional role of direct sympathetic innervation in this process, we surgically denervated sympathetic input to vessels locally by unilaterally cutting the superior cervical ganglion. While the contralateral, nerve‐intact sides still exhibited rhythmicity in both leukocyte adhesion and ICAM‐1 expression, local denervation resulted in a loss of oscillations. Similar results were obtained by administration of beta adrenergic receptor antagonists. Interestingly, when using Ng2Cre x Bmal1flox/flox mice, in which the core clock gene Bmal1 and thus rhythmicity was selectively deleted in arteriolar Ng2+‐pericytes, an ablation of the oscillations was observed in both arteries and veins. Thus, using pharmacological, surgical and genetic approaches, our data point to an important role of arteries in regulating rhythmic leukocyte recruitment to veins.Support or Funding InformationFunded by the German Research Foundation (Emmy Noether SCHE 1645/2‐1 and SFB914 projects B09 and Z03) and the European Research Council (CIRCODE, 635872)

Sympathetic innervation of human muscle spindles.

The aim of the present study was to investigate the presence of sympathetic innervation in human muscle spindles, using antibodies against neuropeptide Y (NPY), NPY receptors and tyrosine hydroxylase (TH). A total of 232 muscle spindles were immunohistochemically examined. NPY and NPY receptors were found on the intrafusal fibers, on the blood vessels supplying muscle spindles and on free nerve endings in the periaxial space. TH-immunoreactivity was present mainly in the spindle nerve and vessel. This is, to our knowledge, the first morphological study concerning the sympathetic innervation of the human muscle spindles. The results provide anatomical evidence for direct sympathetic innervation of the intrafusal fibers and show that sympathetic innervation is not restricted to the blood vessels supplying spindles. Knowledge about direct sympathetic innervation of the muscle spindle might expand our understanding of motor and proprioceptive dysfunction under stress conditions, for example, chronic muscle pain syndromes.

Alterations of cAMP-dependent signaling in dystrophic skeletal muscle

Autonomic regulation processes in striated muscles are largely mediated by cAMP/PKA-signaling. In order to achieve specificity of signaling its spatial-temporal compartmentation plays a critical role. We discuss here how specificity of cAMP/PKA-signaling can be achieved in skeletal muscle by spatio-temporal compartmentation. While a microdomain containing PKA type I in the region of the neuromuscular junction (NMJ) is important for postsynaptic, activity-dependent stabilization of the nicotinic acetylcholine receptor (AChR), PKA type I and II microdomains in the sarcomeric part of skeletal muscle are likely to play different roles, including the regulation of muscle homeostasis. These microdomains are due to specific A-kinase anchoring proteins, like rapsyn and myospryn. Importantly, recent evidence indicates that compartmentation of the cAMP/PKA-dependent signaling pathway and pharmacological activation of cAMP production are aberrant in different skeletal muscles disorders. Thus, we discuss here their potential as targets for palliative treatment of certain forms of dystrophy and myasthenia. Under physiological conditions, the neuropeptide, α-calcitonin-related peptide, as well as catecholamines are the most-mentioned natural triggers for activating cAMP/PKA signaling in skeletal muscle. While the precise domains and functions of these first messengers are still under investigation, agonists of β2-adrenoceptors clearly exhibit anabolic activity under normal conditions and reduce protein degradation during atrophic periods. Past and recent studies suggest direct sympathetic innervation of skeletal muscle fibers. In summary, the organization and roles of cAMP-dependent signaling in skeletal muscle are increasingly understood, revealing crucial functions in processes like nerve-muscle interaction and muscle trophicity.

Ischemic Emergency?

See related article, pp 129–136 Endothelial cells (ECs) constitute the cell layer covering the luminal surface of all of the blood vessels throughout the entire cardiovascular system and, although initially thought of as inert, purely structural components of vessel walls, are now known to play prominent roles in many facets of vascular physiology.1 Among these are angiogenesis and neoangiogenesis, phenomena that rely on EC migration and proliferation, inflammation, immune responses to injury and tissue healing, blood coagulation, regulation of vascular smooth muscle cell proliferation, atherosclerosis, and atherotic plaque rupture, and, last but not least, ECs are critical regulators of vascular tone via release of a vast plethora of vasoactive agents that promote either constriction or relaxation of the arterial wall smooth muscle, thus exerting important control on systemic blood pressure.1,2 EC function is, in turn, fine tuned by several hormones, whose receptors ECs express on their membranes. Among these hormones are the catecholamines (CAs), which have been known to cause vasoconstriction via α1- (and α2-) adrenergic receptors (ARs) and vasodilation via β2ARs present in vascular smooth muscle.3 However, ARs are also present in EC membranes, per se, and presumably respond to circulating norepinephrine (NE) and epinephrine (Epi), because ECs, unlike vascular smooth muscle, are devoid of sympathetic innervation.1 The circulating CAs, dopamine, NE, and Epi, are synthesized from the amino acid precursor l-tyrosine. Tyrosine hydroxylase catalyzes the first and rate-limiting step in CA biosynthesis, converting l-tyrosine to l-dihydroxyphenylalanine, which, in turn, produces dopamine via decarboxylation by aromatic l-amino acid decarboxylase. In (nor)adrenergic neurons and in the adrenal medulla, …

Mice Lacking Adrenergic Signaling Have Normal Cochlear Responses and Normal Resistance to Acoustic Injury but Enhanced Susceptibility to Middle-Ear Infection

The vasculature and neurons of the inner ear receive adrenergic innervation from the cervical sympathetic chain, and adrenergic receptors may be expressed by cells of the organ of Corti and stria vascularis, despite a lack of direct sympathetic innervation. To assess the functional role of adrenergic signaling in the auditory periphery, we studied mice with targeted deletion of the gene for dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine to noradrenaline; thus, these mutant mice have no measurable adrenaline or noradrenaline. Dbh (-/-) mice were more susceptible to spontaneous middle-ear infection than their control littermates, consistent with a role for sympathetics in systemic and/or local immune response. At 6-8 weeks of age, cochlear thresholds and suprathreshold responses assessed by auditory brainstem responses and distortion product otoacoustic emissions, as well as light-microscopic morphology, were indistinguishable from controls, if ears with conductive hearing loss were eliminated. Dbh (-/-) mice were no more susceptible to acoustic injury than controls, despite prior reports that sympathectomy reduces noise damage. Dbh (-/-) mice showed enhancement of shock-evoked olivocochlear suppression of cochlear responses, which may arise from the loss of adrenergic inputs to olivocochlear neurons in the brainstem. However, adrenergic modulation of olivocochlear efferents does not mediate the protective effect of contralateral cochlear destruction on ipsilateral response to acoustic overexposure.

Social Stress Enhances Sympathetic Innervation of Primate Lymph Nodes: Mechanisms and Implications for Viral Pathogenesis

Behavioral processes regulate immune system function in part via direct sympathetic innervation of lymphoid organs, but little is known about the factors that regulate the architecture of neural fibers in lymphoid tissues. In the present study, we find that experimentally imposed social stress can enhance the density of catecholaminergic neural fibers within axillary lymph nodes from adult rhesus macaques. This effect is linked to increased transcription of the key sympathetic neurotrophin nerve growth factor and occurs predominately in extrafollicular regions of the paracortex that contain T-lymphocytes and macrophages. Functional consequences of stress-induced increases in innervation density include reduced type I interferon response to viral infection and increased replication of the simian immunodeficiency virus. These data reveal a surprising degree of behaviorally induced plasticity in the structure of lymphoid innervation and define a novel pathway by which social factors can modulate immune response and viral pathogenesis.

Neural–immune interactions: An integrative view of the bidirectional relationship between the brain and immune systems

This review briefly summarizes a part of the relevant knowledge base of neuroimmunology, with particular emphasis on bidirectional neural–immune interactions. These complex systems interact at multiple levels. Both neuroendocrine (the primary hormonal pathway is hypothalamic–pituitary–adrenal axis) and neuronal (direct sympathetic innervation of the lymphoid organs) pathways are involved in the control of the humoral and cellular immune responses. Although, the recent evidence has been made on immunosuppressive effect of acetylcholine-secreting neurons of the parasympathetic nervous system. The immune system, in turn, influences the central nervous system primarily through cytokines. At the molecular level, neuro- and immune signal molecules (hormones, neurotransmitters, neuropeptides, cytokines) or their receptors are member of the same superfamily which enable the mutual neuroimmune communication. Most extensively studied are cytokine-neuropeptide/neurotransmitter interactions and the subcellular and molecular mechanisms of these interactions. At the system (neuroanatomical) level, advances in neural–immune communication have been made in the role of discrete brain areas related to emotionality. The immunoenhancement, including the antiviral and antitumor cytotoxic activity, related to the “brain reward system”, limbic structures and neocortex, offers a new directions for therapy in immune disorders.

Atrial resynchronisation after heart transplant in childhood

Objectives: Exercise capacity is known to be reduced in clinically stable cardiac transplant recipients, there is a substantial attenuation in the peak heart rate response to a maximal exercise effort due to the lack of direct sympathetic innervation of the donor SA node. Recipient SA node can still respond to this stimulation and we hypothesised that resynchronisation of both atria could improve exercise tolerance in these patients.

An investigation of a sympathetic innervation of the vertebral artery in primates: is there a neurogenic substrate for vasoconstriction?

Vasoconstriction of the vertebral artery may be neurogenic in origin. Although the existence of a perivascular sympathetic plexus of the vertebral artery is not in doubt, no method used to date has conclusively demonstrated a direct sympathetic innervation of the vascular smooth muscle cells and, hence, vasomotor function. It was the aim of this study, therefore, to visualise and localise noradrenergic fibres in the wall of the vertebral artery. Intracranial vertebral artery specimens (10 vervet monkeys and 10 baboon vessels) were sectioned (40 mm serial sections) and treated with anti-tyrosine hydroxylase, anti-dopamine b-hydroxylase, and anti-chromogranin-A antibodies. Some evidence of catecholaminergic fibres in the tunica adventitia but not penetrating the external elastic lamina or tunica media of the vertebral artery wall was seen. These findings were confirmed by electron microscopy. It was concluded that although a perivascular sympathetic plexus exists, the vertebral artery of primates was not shown to have a direct sympathetic innervation and a neurogenic vasoconstrictor function is unlikely.

The Maturation of Airway Structure and Function

After completing this article, readers should be able to: 1. Explain the physiologic reasons that immature infants are at a greater risk of mechanical ventilation-induced airway damage than are more mature infants. 2. Describe the age-related differences in airway function during perinatal development. 3. Delineate how differential expression of smooth muscle myosin heavy-chain isoforms affects airway smooth muscle physiology and airway mechanics. 4. Explain how expression of smooth muscle proteins contributes to the functional maturation of airway smooth muscle. Airway formation is one of the earliest events in the development of the respiratory system. However, continued maturation of the airway continues well into postnatal life. With advances in the medical care of increasingly preterm infants, an understanding of developmental airway physiology becomes imperative. This article reviews maturation of the airway and its components as well as their contributions to airway function during development. Airway development in the human begins during the fourth week of gestation when the respiratory diverticulum, or lung bud, branches from the embryonic foregut. The esophagotracheal septum forms and separates the foregut into the esophagus dorsally and the trachea ventrally. Thus, the developing airway is of foregut endodermal origin. Elongation of the respiratory diverticulum forms the trachea; branching forms the main stem bronchi. Growth and elongation continues in the caudal direction under the influence of airway secretions and physical forces. By the end of the 16th week of gestation, branching of the conducting airways is complete. The airway matures initially in the trachea and proceeds distally. Tracheal cartilage begins to form during the seventh week of gestation. Maturation of the distal airway cartilage is not complete until after birth. Epithelial differentiation begins in the trachea during the 10th week of gestation. Together with phasic contractions of the fetal airway smooth muscle, which are present following the 23rd gestational week, lung fluid …

On Sympathetic Innervation of Muscle Spindles of the Frog Rana temporaria

The work is concerned with solution of a questionable problem, whether there exists a direct sympathetic innervation of muscle spindles. On the isolated total preparations of muscle spindles, with the aid of a specific histochemical fluorescent method using glyoxylic acid, revealed is the sympathetic innervation of these structures: adrenergic terminal axons were found both on the intrafusal muscular fibers and the blood vessels supplying the receptor.

Sympathoadrenal system differentially affects photoperiodic changes in humoral immunity of Siberian hamsters (Phodopus sungorus).

Siberian hamsters (Phodopus sungorus) rely on photoperiod as a primary cue to coordinate seasonally appropriate changes in physiology and behaviour. Among these seasonal changes is reduced immune function in short 'winter-like' days, compared to long 'summer-like' days. Previous evidence suggests that immune function is regulated, in part, by the sympathoadrenal system. The precise role of the sympathoadrenal system in regulating photoperiodic changes in immune function, however, remains unspecified. The goal of the present study was to examine the differential contributions of direct sympathetic innervation of immune target tissue, as well as adrenal medullary catecholamines, to photoperiodic changes in immune function in male Siberian hamsters. In Experiment 1, hamsters underwent either bilateral surgical removal of the adrenal medulla (ADMEDx), or sham surgeries, and were maintained in long (LD 16 : 8) or short days (LD 8 : 16). In Experiment 2, hamsters received either surgical denervation of the spleen, or sham surgeries, and were then housed in long or short days. Serum anti-KLH IgG concentrations and splenic norepinephrine (NE) content were determined in both experiments. Short-day hamsters had reduced humoral immunity compared to long-day hamsters. ADMEDx reduced immune function, but only in long-day hamsters. In contrast, splenic denervation reduced humoral immunity, but only in short-day hamsters. Splenic NE content was increased in short days and by ADMEDx. NE content was markedly reduced in denervated hamsters compared to sham-operated hamsters. Collectively, these results suggest that the sympathoadrenal system is associated with photoperiodic changes in immune function.

Direct innervation of white fat and adrenal medullary catecholamines mediate photoperiodic changes in body fat.

Seasonal adjustments in Siberian hamster adiposity are triggered by day length changes [i.e., short "winter-like" days (SDs) elicit body fat decreases vs. long "summer-like" days (LDs)]. These and other white adipose tissue (WAT) mass decreases traditionally have been ascribed to lipolysis triggered by sympathetically mediated, adrenal medullary released epinephrine; however, recent evidence suggests that direct sympathetic innervation of WAT also is important. Therefore, the contributions of WAT sympathetic innervation and adrenal medullary catecholamines to SD-induced decreases in adiposity were tested. Siberian hamsters were surgically bilaterally adrenal demedullated (ADMEDx) or sham ADMEDx, and all had one inguinal WAT (IWAT) pad sympathectomized via locally injected guanethidine, with the contralateral pad serving as a within-animal innervated control. One-half of the hamsters remained in LDs; the remainder was transferred to SDs. Guanethidine and ADMEDx abolished IWAT norepinephrine and adrenal epinephrine contents, respectively. Although sympathetic denervation or ADMEDx alone did not block SD-induced decreases in IWAT mass, their combination did. These results suggest that both adrenal catecholamines and the sympathetic innervation of WAT interact to decrease SD-induced decreased adiposity.

The sympathetic nervous system in white adipose tissue regulation.

Sympathetic stimulation has long been recognized to mobilise fatty acids from white adipose tissue. However, it is now apparent that adipose tissue is not only concerned with energy storage as fat, but is a major endocrine and secretory organ. This change has resulted from the identification of leptin as a hormone of energy balance secreted by white adipose tissue. The sympathetic system is a key regulator of leptin production in white fat. Sympathomimetic amines, cold exposure or fasting (which lead to sympathetic stimulation of white fat), decrease ob gene expression in the tissue and leptin production. On the other hand, sympathetic blockade often increases circulating leptin and ob gene expression, and it is postulated that the sympathetic system has a tonic inhibitory action on leptin synthesis. In rodents this action is through stimulation of, beta3-adrenoceptors. The adrenal medulla (as opposed to the direct sympathetic innervation) has been thought to play only a minor role in the catecholaminergic regulation of white adipose tissue. However, in rodents responses of the leptin system to adrenergic blockade vary with the method used. Changes in leptin and ob gene expression are considerably less using methods of blockade that only effect the terminal adrenergic innervation, rather than medullary secretions as well. Stimulation of the leptin system increases sympathetic activity and hence metabolic activity in many tissues. As well as leptin, other (but not all) secretions from white adipose tissue are subject to sympathetic regulation. In obesity the sympathetic sensitivity of adipose tissue is reduced and this factor may underlie the dysregulation of leptin production and other adipose tissue secretions.

Reply

Harald Groeben, M.D., Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287–279.Hans-Bernd Hopf, M.D., Zentrum f. Klin. Anaesthesiologie, Heinrich-Heine Univ. Dusseldorf Moorenstrasse 5, D-40001 Dusseldorf, Germany.In Reply: — Dicpinigaitis et al. suggest that the results of our body in humans are unexpected in light of recent published studies in humans with cervical spinal cord transections and animal (guinea pig) studies with lidocaine injections directly into the spinal cord. However, we do not think that these findings are contradictory to ours and would like to offer some alternate explanations.First, in humans with cervical spinal cord transsection, sympathetic neural transmission is interrupted anatomically and not, as in our study, by injection of local anesthetic into the thoracic epidural space that result in substantial local anesthetic plasma concentrations. In fact, our study shows that intravenous administration of a local anesthetic resulted in a significant attenuation to inhaled acetylcholine, which was not significantly different from that observed after epidural administration, despite bronchial sympatholysis. Thus, the effect of the local anesthetic per se seems to play a dominant role and must be considered in the interpretation of the observed effects in our study. Therefore, the findings that, in humans with spinal cord transection, bronchial hyperresponsiveness was present is not unexpected, and we agree that this might be explained on the basis of unopposed parasympathetic airway innervation in this specific patient population.Second, the extent of direct sympathetic innervation of the bronchial system varies greatly from species to species. In guinea pigs, cats, and dogs, there is a well developed direct sympathetic innervation of the bronchial system, whereas there is only a rare sympathetic innervation of the human airway. [1] Using autoradiographic techniques, an additional sympathetic innervation of the bronchial system in humans has been shown (mainly glands, vessels, and alveolar walls, but not bronchial smooth muscle) and is assumed to have no functional relevance for airway resistance regulation. [1,2] Finally. Peter J. Barnes (1992) writes in his review about modulation of neurotransmission in airways that, in contrast to guinea pigs, cats, and dogs, there is no adrenergic bronchodilator response to direct nerve stimulation in humans. [3] Thus, results obtained from animal models may not represent the regulation of airway resistance in the human bronchial system.In summary, we do not believe that the arguments raised by Dicpinigaitis et al, are contradictory to our statement that “blockade of pulmonary sympathetic innervation by thoracic epidural anesthesia seems to be of no relevance for airway resistance in humans.”Harald Groeben, M.D., Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287–279.Hans-Bernd Hopf, M.D., Zentrum f. Klin. Anaesthesiologie, Heinrich-Heine Univ. Dusseldorf Moorenstrasse 5, D-40001 Dusseldorf, Germany.(Accepted for publication December 5, 1994).

In vivo beta-adrenergic induction of the unmasking of the uncoupling protein in rat brown fat.

1. In 28 degrees C adapted rats (WA) both cold stress and norepinephrine (NE) led to a 4-fold increase of uncoupling protein dependent proton conductance which was abolished by propranolol (PRO). 2. In 4-day warm re-exposed rats (after 10 days at 5 degrees C) (WR) the same uncoupling by cold stress was observed but the NE effect was lower. Uncoupling by cold stress was not abolished by PRO. 3. In WR rats, uncoupling was not due to the involvement of an alpha-adrenergic pathway. 4. Both beta-agonist isoproterenol and beta 3-agonists BRL 35135A and ICI D7114 led to high levels of unmasking. 5. Interscapular brown adipose tissue surgical denervation, which abolished cold stress unmasking both in WA and, WR rats, indicates a mediation by direct sympathetic innervation. 6. Depending on the thermal history of the rat, the possibility that unmasking by cold stress could be mediated by different types of beta-receptors is discussed.