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PubMed1991

Effect of denervation or unweighting on GLUT-4 protein in rat soleus muscle.

The purpose of this study was to test the hypothesis that the decreased capacity for glucose transport in the denervated rat soleus and the increased capacity for glucose transport in the unweighted rat soleus are related to changes in the expression of the regulatable glucose transporter protein in skeletal muscle (GLUT-4). One day after sciatic nerve sectioning, when decreases in the stimulation of soleus 2-deoxyglucose (2-DG) uptake by insulin (-51%, P less than 0.001), contractions (-29%, P less than 0.05), or insulin and contractions in combination (-40%, P less than 0.001) were observed, there was a slight (-18%, NS) decrease in GLUT-4 protein. By day 3 of denervation, stimulation of 2-DG uptake by insulin (-74%, P less than 0.001), contractions (-31%, P less than 0.001), or the two stimuli in combination (-59%, P less than 0.001), as well as GLUT-4 protein (-52%, P less than 0.001), was further reduced. Soleus muscle from hindlimb-suspended rats, which develops an enhanced capacity for insulin-stimulated glucose transport, showed muscle atrophy similar to denervated soleus but, in contrast, displayed substantial increases in GLUT-4 protein after 3 (+35%, P less than 0.05) and 7 days (+107%, P less than 0.001). These results indicate that altered GLUT-4 expression may be a major contributor to the changes in insulin-stimulated glucose transport that are observed with denervation and unweighting. We conclude that muscle activity is an important factor in the regulation of GLUT-4 expression in skeletal muscle.

Animals↗
PubMed1995

Effect of multiple denervations on the exercise hyperpnea in awake ponies.

In three previously reported studies, we had documented that the normal exercise hyperventilation in ponies is accentuated by carotid body denervation (CBD), not affected by hilar nerve pulmonary vagal denervation (HND), and mildly attenuated by spinal cord ablation of the dorsal lateral columns at L2 (SA). In the present study, we hypothesized that if redundancy of control existed in exercising ponies, then multiple denervations of theoretically important pathways in the same animal might attenuate the ventilatory response to exercise in a way not predictable by the individual lesion experiments alone. There were three major findings in the various combinations of CBD, HND, and SA in ponies during treadmill exercise. First, the combination of CBD with HND or SA resulted generally in an accentuation of the hypocapnia during exercise that was predictable on the basis of CBD alone. However, in one pony that showed a hypercapnic exercise response after SA alone, CBD subsequently caused a greater exercise hypercapnia. Second, HND in a CBD or SA pony did not affect the exercise arterial PCO2 response, which is consistent with previous data showing the lack of an HND effect in otherwise intact ponies. Third, in ponies with all three denervations together, the predominant response was an increase, not a decrease, in the exercise hyperventilation; this increase was greater than that predicted from the individual lesions. We conclude that these data do not provide evidence of redundancy in mechanism for the exercise hyperpnea other than instances of carotid chemoreceptor error sensing when hypercapnia occurs during exercise.

Afferent Pathways↗
PubMed1997

Na+ channel and acetylcholine receptor changes in muscle at sites distant from burns do not simulate denervation.

Muscle weakness and aberrant responses to neuromuscular relaxants after burn injury are associated with upregulation of acetylcholine receptors (AChRs). Typically, these functional, pharmacological, and biochemical changes occur after denervation, in which transcriptionally mediated qualitative changes in AChRs and Na+ channels and of myogenic regulatory proteins MyoD and myogenin also occur. This study in rats, by an examination of changes in the above-enumerated proteins or their transcripts in the gastrocnemius muscle distant from the burn, verifies whether a denervation-like state exists after burns. Scatchard analysis of [3H]saxitoxin binding revealed no changes in the affinity (K(d)) and total number (B(max)) of Na+ channels between control and burn-injured animals at both 7 and 14 days after injury. The mRNA levels of the immature proteins, SkM2 of the Na+ channels and the gamma-subunits of AChRs, the increase of which is pathognomic of denervation, were assessed by Northern analysis and were unchanged. The transcripts of mature Na+ channels, SkM1, were significantly increased at day 14 after the burn (1.24 +/- 0.10 in burn-injured vs. 1.06 +/- 0.12 in sham animals, arbitrary units, P = 0.006). Although MyoD levels were increased in burn-injured animals at 14 days (0.21 +/- 0.02 vs. 0.15 +/- 0.07 arbitrary units, P = 0.05), myogenin levels were unaltered. The absence of changes in AChR transcripts, including alpha-, delta-, and gamma-subunits, indicates that the upregulation of AChR in burns is not transcriptionally mediated. The unaltered levels of transcripts of myogenin, SkM2 of Na+ channels and gamma-subunit of AChR, confirm that there is no denervation-like prejunctional (nerve-related) component to explain the muscle weakness or the upregulation of AChRs at sites distant from burns.

Animals↗
PubMed1997

Effects of renal denervation on cardiovascular and renal responses to ACE inhibition in conscious lambs.

Effects of renal denervation on cardiovascular and renal responses to ACE inhibition in conscious lambs. J. Appl. Physiol. 83(2): 414-419, 1997.-Cardiovascular and renal effects of either the angiotensin-converting enzyme inhibitor captopril or vehicle were measured in chronically instrumented lambs in the presence (intact; n = 6) and absence of renal sympathetic nerves (denervated; n = 5) to determine whether there was an interaction between the renin-angiotensin system and renal sympathetic nerves early in life. Captopril caused a similar decrease in mean arterial pressure (P < 0. 001) in intact and denervated lambs, predominantly through a decrease in diastolic pressure. Heart rate was increased from 177 +/- 34 to 213 +/- 22 (SD) beats/min during captopril compared with vehicle infusion in intact lambs. In denervated lambs, basal heart rates were elevated to 218 +/- 33 beats/min; there was no further increase in heart rate during captopril compared with vehicle infusion. Captopril infusion caused a decrease in renal vascular resistance but only in the absence of renal nerves. These findings provide evidence to suggest that early in life there is an interaction between renal sympathetic nerves and the renin-angiotensin system in regulating renal hemodynamics and the baroreflex control of the heart.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Plasticity in the control of breathing following sensory denervation.

The purpose of this manuscript is to review the results of studies on the recovery or plasticity following a denervation- or lesion-induced change in breathing. Carotid body denervation (CBD), lung denervation (LD), cervical (CDR) and thoracic (TDR) dorsal rhizotomy, dorsal spinal column lesions, and lesions at pontine, medullary, and spinal sites all chronically alter breathing. The plasticity after these is highly variable, ranging from near complete recovery of the peripheral chemoreflex in rats after CBD to minimal recovery of the Hering-Breuer inflation reflex in ponies after LD. The degree of plasticity varies among the different functions of each pathway, and plasticity varies with the age of the animal when the lesion was made. In addition, plasticity after some lesions varies between species, and plasticity is greater in the awake than in the anesthetized state. Reinnervation is not a common mechanism of plasticity. There is evidence supporting two mechanisms of plasticity. One is through upregulation of an alternate sensory pathway, such as serotonin-mediated aortic chemoreception after CBD. The second is through upregulation on the efferent limb of a reflex, such as serotonin-mediated increased responsiveness of phrenic motoneurons after CDR, TDR, and spinal cord injury. Accordingly, numerous components of the ventilatory control system exhibit plasticity after denervation or lesion-induced changes in breathing; this plasticity is uniform neither in magnitude nor in underlying mechanisms. A major need in future research is to determine whether "reorganization" within the central nervous system contributes to plasticity following lesion-induced changes in breathing.

Animals↗
PubMed2002

Time course of changes in lipoprotein lipase activity in rat skeletal muscles during denervation-reinnervation.

The effects of denervation-reinnervation after sciatic nerve crush on the activity of extracellular and intracellular lipoprotein lipase (LPL) were examined in the soleus and red portion of gastrocnemius muscles. The activity of both LPL fractions was decreased in the two muscles within 24 h after the nerve crush and remained reduced for up to 2 wk. During the reinnervation period, LPL activity was still reduced in the soleus and started to increase only on the 40th day. In the red gastrocnemius, LPL activity increased progressively with reinnervation, exceeding control values on the 30th day post-crush. The LPL activity in the soleus from the contralateral to denervated hindlimb was also affected, being increased on the postoperation day and then gradually decreased during the following days. In conclusion, the time course of changes in muscle LPL activity after nerve crush confirmed the predominant role of nerve conduction in controlling muscle potential to take up free fatty acids derived from the plasma triacylglycerols. However, other factors, such as muscle fiber composition and the fiber transformation, should also be considered in this aspect of the denervation-reinnervation process. Moreover, it was found that denervation of muscles from one hindlimb may influence LPL activity in muscles from the contralateral leg.

Animals↗
PubMed2005

Changes in corticospinal efficacy contribute to the locomotor plasticity observed after unilateral cutaneous denervation of the hindpaw in the cat.

We used microwire electrodes chronically implanted into the hindlimb representation of the motor cortex as well as into the pyramidal tract to test the hypothesis that the corticospinal system contributes to the locomotor plasticity that is observed after cutaneous denervation of the cat hindpaw. A total of 23 electrodes implanted into the motor cortex in three cats trained to walk on a treadmill produced phase-dependent, short-latency, twitch responses in hindlimb flexor and extensor muscles during locomotion. After a unilateral cutaneous denervation of the hindpaw, the cats showed transient deficits in locomotion, including a dragging of the hindpaw along the treadmill belt during the swing phase. This deficit rapidly recovered over the course of a few days. The recovery of locomotion was accompanied by an increase in the magnitude of the responses evoked in different muscles by the cortical stimulation at all 23 cortical sites. Response magnitude increased rapidly within the first 1-2 wk postdenervation before attaining a plateau at > or =3 wk. In two cats, for which detailed information was obtained, response magnitude in the knee flexor, semitendinosus (St), was increased by >250% at 14/18 sites (mean increase = 1,235%). Increased responses in the St to stimulation were also observed at two of the four pyramidal tract sites after the denervation but were relatively smaller (max = 593%) than those evoked by the cortical stimulation. We suggest that the denervation produces changes in both cortical and spinal excitability that, together, produce a change in corticospinal efficacy that contributes to the recovery of locomotor function.

Animals↗
PubMed1991

Acute changes in cutaneous receptive fields in primary somatosensory cortex after digit denervation in adult flying fox.

1. Acute effects of permanent and temporary denervation of the flying fox thumb were examined to test the hypothesis that a large area of skin around the cutaneous receptive field of multiunits (MRF) at a locus in primary somatosensory cortex (SI) supplies viable inputs which can be rapidly unmasked by interruption of the dominant input from the area of the MRF. 2. The immediate effect of amputation of the thumb at loci where the original receptive field was entirely removed was to produce large MRFs on adjacent body areas (wrist, forearm, prowing, and finger membranes). Greatly expanded MRFs were also produced when amputation removed only part of the original MRF at a cortical locus. 3. The probable source of input to account for the new receptive fields is the extensive arborization of ascending projections within the somatosensory pathway, which supply a cortical locus with a potential input from a far larger area than is represented in its normal receptive field. The rapidity with which new or expanded fields are seen following denervation indicates that the normally unexpressed inputs around a receptive field are not only potential inputs but are inherently viable. Hence the most likely explanation for the results of this study is that the effect of the denervation is to disrupt an inhibitory influence that normally has the role of shaping the receptive field. 4. Temporary anesthesia of all or part of a MRF produced similar initial effects to amputation. When responsiveness returned to the locally anesthetized area (after 10-30 min), an expanded MRF persisted for a short time after which the boundaries of the MRF shrank. This rapid reversal suggests that a mechanistic rather than a plastic change is the basis for the acute effect of a small denervation on SI.

Animals↗
PubMed2001

Differential roles of endogenous nitric oxide on neural regulation of basal exocrine pancreatic secretion in intact and denervated pancreas.

BACKGROUND: Autonomic nerves and humoral factors regulate pancreatic secretion. Nerves containing nitric oxide (NO) synthase (NOS) are in close proximity and located within cholinergic, adrenergic and sensory nerve bundles. Yet, the interactive mechanisms between various nerve populations remain elusive. AIMS: To evaluate the role of endogenous NO in basal exocrine pancreatic secretion in the extrinsically denervated rat pancreas. METHODS: Male Sprague-Dawley rats were assigned to 2 groups of 11 animals. The first group of sham-operated animals served as controls. In the second group extrinsic pancreatic innervation was surgically interrupted. One week later, after selective catheterization of the celiac axis and the bile-pancreatic duct, the animals received intra-arterial infusions of NG-nitro-L-arginine (L-NNA; 0.48 mg/kg b.w./h) followed by intra-arterial infusions of L-arginine (110 mg/kg b.w./h). Total protein and amylase were measured in bile-pancreatic secretions collected at 15-min intervals. RESULTS: In controls, total protein and amylase output showed a biphasic secretion pattern with an increase during L-NNA infusion followed by a decrease when the infusion ceased and further augmentation 1 h later. In denervated animals, L-NNA caused a sustained decrease in pancreatic secretion followed by an increase 1 h later. Infusion of L-arginine at the time of maximum decrease slowed the second phase of protein and amylase output in sham-operated rats, but accentuated the onset of secretion in denervated animals. CONCLUSION: Inhibition of endogenous NO release was shown to increase baseline secretion in the intact pancreas. Superposition of extrinsic denervation on neural NOS-blockade decreased basal exocrine secretion, indicating that intra-pancreatic NO release is regulated by extra-pancreatic nerves.

Amylases↗
PubMed2003

A role for protein kinase C in the supersensitivity of the rat vas deferens following chronic surgical denervation.

Chronic surgical denervation of the rat vas deferens leads to an enhanced contractile response of the tissue to norepinephrine in vitro. Norepinephrine produces a higher rate of protein kinase C translocation to the particulate fraction of denervated tissues as compared with the paired, control vas deferens. Diacylglycerol generation in response to norepinephrine and contractile responses to phorbol diacetate were not altered by chronic denervation of the vas deferens. However, the contractile response to norepinephrine in these tissues was less susceptible to the inhibitory effects of the calcium channel blocker nifedipine. A potential role of protein kinase C in sensitizing the contractile apparatus to mobilized calcium in denervation supersensitivity is discussed.

Animals↗
PubMed2005

Myosin loss in denervated rat soleus muscle after dexamethasone treatment.

OBJECTIVE: Critical illness myopathy (CIM) is an acute myopathy that appears in the setting of critical illness or during exposure to corticosteroids and neuromuscular blocking agents. Its pathological feature is selective loss of thick myosin filaments. Our aim is to gain further insight into the pathomechanism of myosin loss in this myopathy. METHODS: To clarify the expression of myosin heavy chain (MHC) and ubiquitin ligase atrogin-1 in this myopathy, histological, immunohistochemical, SDS-PAGE, and semiquantitative reverse transcriptase-polymerase chain reaction studies were performed on innervated and denervated rat soleus muscles after saline and dexamethasone treatments. RESULTS: Denervated muscles from dexamethasone-treated rats showed marked MHC loss. The mRNA expression of ubiquitin ligase atrogin-1 was significantly increased in denervated dexamethasone-treated muscles, suggesting that the ubiquitin-proteasome pathway plays an important role in muscular wasting in CIM. Furthermore, mRNA levels of MHC I, a myosin isoform, were decreased in the denervated dexamethasone-treated muscles. CONCLUSION: Our findings suggest that an altered transcription rate of myosin, as well as the upregulation of multiple ubiquitin ligases, may be responsible for selective myosin loss in this myopathy.

Animals↗
PubMed1988

Stimulation of pro-opiomelanocortin gene expression by glucocorticoids in the denervated rat intermediate pituitary gland.

The effect of frontal deafferentation of the medial basal hypothalamus on pro-opiomelanocortin (POMC) gene expression was studied in the intermediate lobe (IL) and anterior lobe (AL) of the pituitary gland in the absence and presence of corticosterone (CORT). The lesion in the basal hypothalamus removed neural inputs to the IL and induced the glucocorticoid receptor (GR) in this tissue. The GR was visualized in the denervated IL by immunocytochemistry. Induction of the GR had a slow onset and was detectable at 3 weeks after lesion, but not at one week after the lesion. In order to study the effect of IL denervation on pro-opiomelanocortin (POMC) gene expression, the level of messenger RNA specifically encoding POMC was measured 1 and 3 weeks after lesion, in the IL and AL. In adrenalectomized (ADX) animals, the changes in POMC mRNA levels were not significant 1 week after lesion in the IL. Three weeks after denervation there was a 3-fold decrease in POMC mRNA in the IL in ADX rats which was blocked by chronic CORT replacement via subcutaneously implanted pellets. In the AL, CORT reduced the level of POMC gene expression in both the lesioned and control animals. It is concluded that (1) removal of neural input induces GR in the denervated IL cells; (2) with the appearance of the GR, POMC gene expression in the IL becomes sensitive to circulating glucocorticoids; (3) under these conditions, CORT may stimulate POMC gene expression in the IL as opposed to its inhibitory effect in the AL.

Adrenalectomy↗
PubMed1983

Effect of denervation or castration on ultrastructural and histochemical properties of feline bulbocavernosus muscle.

The histochemical and ultrastructural changes in the mature feline bulbocavernosus muscle (BCM) induced after 10 days of denervation or castration were compared. Control BCM, denervated BCM, and BCM from castrated cats reacted similarly for myosin ATPase (predominantly dark staining) and for succinic dehydrogenase (predominantly high). Staining for phosphorylase was decreased in the denervated BCM and BCM from castrated cats. Intrafiber lipid content was reduced after denervation or castration. The appearance of lysosome-like structures in BCM from both treatment groups was the most obvious ultrastructural alteration. Other ultrastructural changes were focal and infrequent.

Animals↗
PubMed1977

Effect of chronic denervation on the activities of monoamine oxidase and catechol-O-methyl transferase and on the contents of noradrenaline and adenosine triphosphate in the rabbit ear artery.

When assayed on homogenates of the rabbit ear artery up to 192 h after sympathetic denervation, the activity of monoamine oxidase (MAO) showed a small but significant decrease (maximum 9%). The activity of catechol-O-methyl transferase (COMT) appeared unchanged, although it is possible that the small and variable nature of this enzyme activity compared with that of MAO may have masked a comparable effect of denervation. The maximum decreases in noradrenaline (NA) and adenosine triphosphate (ATP) contents were greater than 90% at 48 h, and 32% at 96 h after denervation. These results confirm the presence of neuronal as well as extra-neuronal MAO, and also the presence of extraneuronal comt in this artery. The decline in ATP contents after denervation suggest that part of the ATP is neuronal. However, the estimated ratio of NA to neuronal ATP is far in excess of that reported for isolated noradrenaline storage vesicles, suggesting that the major portion of the neuronal ATP was not present in these vesicles.

Adenosine Triphosphate↗
PubMed1979

Kinetics of alpha-adrenoreceptor blockade by phentolamine in the normal and denervated rabbit aorta and rat vas deferens.

The rates of onset and offset of alpha-adrenoreceptor blockade by phentolamine (5 X 10(-7) M) have been studied on the normal and denervated rabbit aorta and rat vas deferens. Removal of the adventitia with its accompanying sympathetic nerve component results in an approximately threefold increase in the rate of onset of alpha-adrenoreceptor blockade by phentolamine in the rabbit aorta. The rate of offset of blockade by the antagonist on the aorta is likewise faster after the adventitia has been removed (approximately threefold faster for loss of 90% of the antagonist from the region of the receptors). This effect is not likely to be attributed to the absence of sympathetic nerve terminals since surgical denervation of the rat vas deferens has no effect on the kinetics of receptor blockade in this densely innervated organ. These data suggest that the adventitia of the rabbit aorta may serve as a diffusion barrier which limits the antagonist's access to, and efflux from, the region of the receptors. The dissociation constant of phentolamine (calculated from the equilibrium dose ratio) on the alpha-adrenoreceptor is unaltered by denervation in either tissue and is identical in both tissues. It is suggested that alpha-adrenoreceptors in the rabbit aorta and rat vas deferens are of a single type and are not significantly affected, with respect to antagonist affinity, by denervation.

Animals↗
PubMed1976

Autonomic nervous system and arrhythmias: studies in the transplanted denervated human heart.

The function of the cardiac autonomic nervous system (ANS) was evaluated by comparison of normal subjects with cardiac transplant recipients. By use of standard intracardiac His bundle recording techniques, the following conclusions regarding basic cardiac electrophysiology were drawn: (1) the sinus node functions normally at rest despite autonomic denervation; (2) the AV node does not show the expected decrease in functional refractory period with increased heart rate in the denervated state, and (3) the adrenergic receptor of the cardiac conduction system does not depend upon autonomic innervation to function normally. Electrophysiologic studies of digitalis demonstrated: (1) in therapeutic doses, the AV nodal blocking effect of digitalis is autonomically mediated; (2) sinus node slowing by digitalis also requires an intact autonomic innervation. Arrhythmia analysis in 47 transplant patients revealed an increased incidence of ventricular arrhythmias in autonomic cardiac denervation. In addition, sudden death in the ischemic denervated heart does occur, weakening the concept of a primary role of the cardiac ANS in this phenomenon.

Arrhythmias, Cardiac↗
PubMed1989

Characteristics of rat kidney dopamine receptors and the effects of renal denervation and dopamine infusion on these receptors.

The characteristics of dopamine receptors, as well as the effects of denervation and dopamine infusion on dopamine receptors were studied using the radiolabeled receptor assay of [3H]-spiperone on rat kidney membrane preparations. The rat renal cortex was found to have a single class of [3H]-spiperone binding sites with a dissociation constant (Kd) of 13.5 +/- 2.2 nM. However, neither sulpiride nor serotonin strongly interacted with [3H]-spiperone binding, suggesting that DA1 receptors were predominant in the rat renal cortex. Denervation was performed by surgically stripping the nerves from the renal artery and coating them with 10% phenol. Chronic denervation had no significant effect on the affinity or maximum binding capacity of the renal dopamine receptors, although diuresis and the disappearance of catecholamine fluorophores in the denervated rats were observed. Chronic infusion of dopamine was performed using an osmotic minipump, resulting in a decrease in the number of rat kidney dopamine receptors. These results suggest that the dopamine receptor subtype in the renal cortex was mainly DA1, and that the major source of dopamine which affected the dopamine receptors in the rat kidney was not the nerve ending, but rather the circulation.

Animals↗
PubMed1997

Effects of combined carotid sinus and aortic depressor nerve denervations in neonatal rat pups.

Denervation of the major peripheral chemo- and barosensory organs of neonatal mammals is known to produce age-dependent effects on mortality and on respiratory and cardiovascular functions. In the current series of experiments, these phenomena were more fully characterized in the young rat. 8- to 9-day-old rats showed few effects of combined carotid sinus and aortic depressor nerve (CSAD) denervation. During the days following surgery, these animals maintained normal body temperatures, had relatively normal weight gain, little cardiorespiratory disruption, and none died. Denervation at earlier ages (postnatal days 3-4 or 0-1) resulted in considerable mortality, 24 and 59%, respectively. In addition, body temperatures were lower, and the weight gain was impaired in the denervated pups as compared with controls, and these effects were more severe in the CSAD nonsurvivors than in the survivors. Also, nonsurvivors had much more severe disruptions of cardiorespiratory patterns measured 24-96 h after surgery than did CSAD survivors. Twenty-four hours after surgery, pups that later died could be identified based on low heart rates and long inspiratory times. CSAD survivors maintained a pattern of moderate cardiorespiratory disruption as compared with controls. Finally, our results indicate that the additional stress of subcutaneous electrocardiography lead implantation and/or daily maternal separation for cardiorespiratory recording increased the mortality in the 3- to 4-day-old CSAD pups from 11 to 40%.

Age Factors↗