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PubMed1982

Chronic denervation of rat diaphragm: selective maintenance of adult fast myosin heavy chains.

After long-term denervation in mixed rat muscles there is a selective loss of slow myosin. The bidimensional electrophoretic pattern of light chains and the results of preliminary studies on heavy chains have left open the question of whether the nature of the residual fast-like myosin is of the immature or adult type. We have further investigated chronically denervated myosin by (1) electrophoresis in nondissociating conditions; (2) acidic electrophoresis of the heavy chains; and (3) proteolytic mapping of the heavy chains. These techniques clearly distinguish adult myosins from those present in immature muscles. Using these criteria, myosin from the chronically denervated diaphragm is of an adult type, even though the presence of trace amounts of embryonic myosin cannot be excluded. The contractile properties also indicate that chronically denervated hemidiaphragm is more similar to an adult fast muscle than to an immature muscle. The selective maintenance after long-term denervation of fast myosin in adult muscle provides good evidence of the independence of the genetic expression of myosin from a direct neural chemotrophic control.

Aging↗
PubMed1984

The effect of denervation on mammalian sarcolemmal proteins and glycoproteins.

The effects of surgical denervation on proteins and glycoproteins of sarcolemmal membranes have been investigated using sarcolemmal fractions prepared from mixed rat muscles. Denervation did not cause any gross change in the protein composition but some consistent quantitative changes were detected. Denervation caused a significant increase in the binding of 125I-labeled concanavalin A (ConA), Ricinus communis agglutinin (RCA120), and wheat germ agglutinin (WGA) to intact membranes. This increased binding appears to be brought about by two mechanisms: the synthesis of more binding-sites with the same apparent KD and the unmasking of previously cryptic binding sites. The activity of sialyl-, galactosyl-, and N-acetylglucosaminyltransferases in the sarcolemmal fractions increased, whereas fucosyl-glycoprotein-transferase activity decreased following denervation. Kinetic analysis of the sialyl- and galactosyltransferase activities showed that the change was due to an increase in Vmax with no change in Km. These results are consistent with an increase in the turnover of sarcolemmal glycoproteins following denervation.

Animals↗
PubMed1984

Axonal transport blockade and denervation have qualitatively different effects upon skeletal muscle metabolism.

The activity and isoenzyme pattern of muscle lactic dehydrogenase (LDH) was measured at different times after axonal transport blockade by colchicine or after denervation. After denervation, total LDH activity decreased and the isoenzyme pattern was altered, LDH-1 being the most affected form. In contrast, after axonal transport blockade there was a decrease in LDH activity but the isoenzyme pattern was not modified. Denervation abolishes both nerve-evoked muscle activity and the release of neuro trophic substances from the nerve whereas colchicine blocks axonal transport without affecting the nerve capacity to conduct action potentials or neuromuscular transmission. It is then concluded that nerve-evoked muscle activity is the most important factor in the regulation of muscle LDH isoenzyme distribution. On the other hand, muscle metabolism can also be regulated by axonally transported molecules. The results presented here show that there is a qualitative difference between the effects of denervation and those of axonal transport blockade upon the muscle, since only denervation altered the isoenzyme pattern of muscle LDH.

Animals↗
PubMed2005

Proteomic analysis of rat laryngeal muscle following denervation.

Laryngeal muscle atrophy induced by nerve injury is a major factor contributing to the disabling symptoms associated with laryngeal paralysis. Alterations of global proteins in rat laryngeal muscle following denervation were, therefore, studied using proteomic techniques. Twenty-eight adult Sprague-Dawley rats were divided into normal control and denervated groups. The thyroarytenoid (TA) muscle was excised 60 days after right recurrent laryngeal nerve was resected. Protein separation and identification were preformed using 2-DE and MALDI-MS with database search. Forty-four proteins were found to have significant alteration in expression level after denervation. The majority of these proteins (57%), most of them associated with energy metabolism, cellular proliferation and differentiation, signal transduction and stress reaction, were decreased levels of expression in denervated TA muscle. The remaining 43% of the proteins, most of them involved with protein degradation, immunoreactivity, injury repair, contraction, and microtubular formation, were found to have increased levels of expression. The protein modification sites by phosphorylation were detected in 22% of the identified proteins that presented multiple-spot patterns on 2-D gel. Significant changes in protein expression in denervated laryngeal muscle may provide potential therapeutic strategies for the treatment of laryngeal paralysis.

Animals↗
PubMed2002

Facilitation of dopamine-mediated locomotor activity in adult rats following cholinergic denervation.

The dopamine hypothesis of schizophrenia postulates hyperactivity of dopaminergic neurotransmission in the mesolimbic system. However, the possible underlying causes for this dopaminergic overfunction are not well understood. Therefore, the main aim of this study was to examine the effect of central cholinergic denervation on dopamine-mediated functions. We also examined the effect of neonatal cholinergic denervation upon adult brain function. The immunotoxin 192 IgG-saporin causes severe lesions of the basal forebrain cholinergic system when infused into the lateral ventricles by targeting neurons expressing the p75 neurotrophin receptor. The toxin may also damage p75-expressing Purkinje neurons in the cerebellum. We have compared the behavioral effects of intracerebroventricular injections of 192 IgG-saporin to adult rats with that of injections to neonate rats. As expected, adult treated rats displayed an almost complete cholinergic denervation of forebrain corticohippocampal areas concomitant with a marked impairment in the Morris water maze. When tested as adults, neonatally treated animals had a less complete cholinergic denervation and showed lesser impairments in water maze behaviors. Interestingly, adult treated rats showed increased spontaneous horizontal activity and a remarkable increase in locomotor response to d-amphetamine as evidenced by increased horizontal and vertical activity. There were no marked changes of spontaneous or drug-induced locomotor activity in adult rats treated with 192 IgG-saporin as neonates. These results suggest that cholinergic denervation of the forebrain causes a marked enhancement of behavioral responses related to dopaminergic activity, probably mainly mediated presynaptically. However, it cannot be fully excluded that damage to noncholinergic systems, e.g., Purkinje cells, might contribute to the effects. The striking overreaction to dopaminergic stimuli, presumably caused by the cholinergic deficit, is discussed in relation to the suggested role of cholinergic malfunctioning in schizophrenia.

Aging↗
PubMed2002

FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic schwann cell denervation.

Poor functional recovery after peripheral nerve injury is attributable, at least in part, to chronic motoneuron axotomy and chronic Schwann cell (SC) denervation. While FK506 has been shown to accelerate the rate of nerve regeneration following a sciatic nerve crush or immediate nerve repair, for clinical application, it is important to determine whether the drug is effective after chronic nerve injuries. Two models were employed in the same adult rats using cross-sutures: chronic axotomy and chronic denervation of SCs. For chronic axotomy, a chronically (2 months) injured proximal tibial (TIB) was sutured to a freshly cut common peroneal (CP) nerve. For chronic denervation, a chronically (2 months) injured distal CP nerve was sutured to a freshly cut TIB nerve. Rats were given subcutaneous injections of FK506 or saline (5 mg/kg/day) for 3 weeks. In the chronic axotomy model, FK506 doubled the number of regenerated motoneurons identified by retrograde labeling (from 205 to 414 TIB motoneurons) and increased the numbers of myelinated axons (from 57 to 93 per 1000 microm2) and their myelin sheath thicknesses (from 0.42 to 0.78 microm) in the distal nerve stump. In contrast, after chronic denervation, FK506 did not improve the reduced capacity of SCs to support axonal regeneration. Taken together, the results suggest that FK506 acts directly on the neuron (as opposed to the denervated distal nerve stump) to accelerate and promote axonal regeneration of neurons whose regenerative capacity is significantly reduced by chronic axotomy.

Animals↗
PubMed1998

Neuropeptide denervation alters both the elicitation and induction phases of contact hypersensitivity in mice.

The effects of permanent disruption of neuropeptide transmission on the induction (i.e., sensitization) and elicitation (i.e., challenge) phases of contact hypersensitivity (CHS) are described. BALB/c mice were chemically denervated of neuropeptide (i.e., tachykinin) containing sensory C fibers by an acute injection of capsaicin (50 mg/kg) on postnatal day (PND) 2 to 3. As young adults (PND 45-60), these mice and their control littermates were sensitized by topical application of 0.1% 2,4-dinitrofluorobenzene (DNFB) or vehicle. Treatment groups generated from this exposure regimen consisted of untreated, controls (O/O), denervated, controls (CAP/O), untreated, sensitized (O/DNFB), and denervated, sensitized (CAP/DNFB). The elicitation phase of CHS was evaluated in these animals by measuring ear thickness in response to a DNFB challenge. In DNFB-sensitized groups, ear thickness was significantly increased over controls but was additionally increased 2.4-fold in CAP/DNFB compared to O/DNFB mice. The induction phase of CHS was next assessed in young adult mice by measuring lymph node cell (LNC) proliferation. For this, mice were sensitized for 3 consecutive days before their draining, auricular nodes were removed. The LNC were dissociated and cultured for 24 h with tritiated thymidine to assess LNC proliferation. As expected, significantly higher numbers of LNC occurred in both DNFB-sensitized groups (CAP/DNFB, O/DNFB) compared to the unsensitized, controls (CAP/O, O/O). However, LNC proliferation in CAP/DNFB was significantly higher than O/DNFB animals. Flow cytometry on similarly exposed mice failed to demonstrate any significant difference in the population of CD4CD8 or CD3CD45R LNC cells from neuropeptide-denervated (CAP/O, CAP/DNFB) mice or their respective treatment mates (O/O, O/DNFB), suggesting that alterations in T or B cell populations did not underlie these changes. Finally, cytokine release from the LNC from these treatment groups was examined. For this, the auricular lymph nodes were removed from animals, 2 to 4 h after the animals were administered a single application of a sensitizing concentration (0.1%) of DNFB or acetone vehicle. LNC, dissociated from these nodes, were cultured for 24 h. The nutrient media was removed from these cultured cells and examined for the release of proinflammatory cytokines, interleukin (IL)-1beta, IL-2 and tumor necrosis factor (TNF)alpha, by ELISA. There were no significant increases in IL-2. However, IL-1beta release was significantly increased in CAP/DNFB mice over O/DNFB by 18-fold and by over 30-fold compare to O/O controls. Levels of TNFalpha were significantly increased in both O/DNFB and CAP/DNFB mice over the nonsensitized controls (O/O, CAP/O). CAP/DNFB values were approximately double that of O/DNFB. There was no significant difference in IL-1beta or TNFalpha release between the nonsensitized controls (O/O, CAP/O). Collectively, these data indicate that neuropeptide denervation by neonatal administration of capsaicin alters both the induction and elicitation phases CHS and may modify sensitivity to chemically induced CHS.

Animals↗
PubMed1990

Impaired hemostasis following denervation of the rat spleen.

The possibility that the noradrenergic system might play a role in modulating platelet activation within the spleen was examined. A new microsurgical model for achieving selective denervation of the rat spleen was created. The denervation procedure resulted in a 96% reduction of the norepinephrine content in splenic tissue. One week after splenic denervation, animals were subjected to standardized splenic resection or standardized transection of mesenteric microvessels. The denervation of the spleen was accompanied by a highly significant increase in bleeding time and blood loss at both locations of trauma. Furthermore, platelet function, measured as adenosine diphosphate (ADP)-induced aggregation, decreased significantly after denervation, indicating that platelet aggregation might be modulated by noradrenergic fibres within the spleen.

Adenosine Diphosphate↗
PubMed1996

Morphological changes in the triads and sarcoplasmic reticulum of rat slow and fast muscle fibres following denervation and immobilization.

We observed the morphological features of the membrane systems (sarcoplasmic reticulum, transverse tubules and triads) involved with the excitation-contraction coupling in rat soleus and extensor digitorum longus muscle following two disuse protocols: denervation and immobilization. The immobilized positions were: maximum dorsal flexor (soleus were stretched and extensor digitorum longus were shortened), maximum plantar flexor (soleus were shortened and extensor digitorum longus were stretched), and midway between the dorsal flexor and plantar flexor. The arrangement of the membrane systems was disordered following both disuse conditions. Increases in transverse tubule network were apparent; there were clearly more triads than in normal fibres, and pentadic and heptadic structures (i.e., a close approximation of two or three transverse tubule elements with three or four elements of terminal cisternae of sarcoplasmic reticulum) were frequently appeared following both denervation and immobilization. The most notable difference between the influence of denervation and immobilization on the membrane systems is the time at which the pentads and heptads appeared. They appeared much earlier (1 week after denervation) in denervated than in immobilized (3 or 4 weeks after immobilization) muscle fibres. On the other hand, the frequency of pentads and heptads is clearly related to the fibre type (significantly higher in extensor digitorum longus) and to extent of atrophy. The different influences of immobilization in each leg position suggest that disuse, but with neurotrophic factor(s), influences on the membrane systems were affected by sarcomere length, and the neurotrophic factor(s) and muscle activity were not always necessary to form new membrane systems in disuse skeletal muscle fibres.

Animals↗
PubMed1994

Morphology of experimentally denervated and reinnervated rat facial muscle. I. Histochemical and histological findings.

The morphological changes in rat facial muscles were evaluated after permanent denervation and were compared with findings after immediate reinnervation. Thirty rats underwent transection of the left and right facial nerves immediately followed by hypoglossal-facial nerve anastomosis on the right side (muscular reinnervation) and removal of 8-10 mm of the facial plexus on the left side (permanent muscular denervation). Levator labii muscle samples of both sides were collected sequentially at 2, 6, 7, 10, 20, and 24 weeks after surgery and submitted to routine histological and enzyme histochemical staining procedures. In normal levator labii muscles a typical "chessboard" pattern was found, with type I fibers being smaller than type II fibers. These latter fibers also were more prevalent than the type I fibers. Among the type II fiber subtypes, the type IIB fibers were larger and more frequent. Two weeks after surgery, there were no differences between denervated facial muscles and those undergoing reinnervation. Both showed atrophic myofibers among normal-sized fibers and slight fibrosis. Those muscles denervated for more than 2 weeks displayed increasing fiber atrophy with frequent loss of typability, as well as proliferation of connective tissue and fat cells in perimysial and endomysial sites. After denervation for 20 weeks only a few atrophic fibers were found in wide areas of fibrosis and fat cells. Following nerve anastomosis the reinnervated levator labii muscle showed much less fiber atrophy. Regrowth to normal fiber diameters was found with only a few atrophic myofibers 10 weeks after anastomosis although a moderate fibrosis predominated at perimysial sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1992

Is neuropeptide Y co-released with catecholamines in experimental arterial hypertension following sinoaortic denervation?

The release of catecholamines and their coneurotransmitter neuropeptide Y (NPY) was investigated in conscious dogs with neurogenic arterial hypertension elicited by sinoaortic denervation. One month after denervation, an elevation of catecholamine levels (measured by HPLC) without elevation of NPY-like immunoreactivity (NPY-LI) levels in plasma (evaluated by RIA) has been found. This dissociation could be explained by 1) a transient release of NPY during the first weeks after surgery, 2) a depletion of neuronal NPY due to the permanent sympathetic stimulation, or 3) an insufficient increase in sympathetic tone. To test these hypotheses, we investigated the time courses of catecholamine and NPY-LI levels in arterial plasma during the first five weeks after sinoaortic denervation and responses to yohimbine (an alpha 2 antagonist which enhances transmitter release). Resting NPY-LI levels in plasma remained normal during the first five weeks after sinoaortic denervation. In normal dogs, a high dose of yohimbine (0.5 mg/kg i.v.) elevated both catecholamine (6-fold) and NPY-LI levels (1.5-fold), whereas a lower dose (0.05 mg/kg i.v.) induced a two fold elevation of catecholamine levels without changing NPY-LI concentrations. In sinoaortically denervated dogs, yohimbine elicited elevation of both catecholamines and NPY-LI whatever the dose used. Thus, neurogenic arterial hypertension in dogs seems to involve catecholamines but not NPY. Moreover, the present work suggests that a high level of sympathetic stimulation is required for a co-release of catecholamines and NPY.

Animals↗
PubMed1988

Changes in surviving nerve fibers associated with submucosal arteries following extrinsic denervation of the small intestine.

The neuropeptide content of nerve fibers associated with submucosal arteries in the small intestine of guinea pigs was studied in whole-mount preparations using immunohistochemical methods. Tissues were obtained from normal animals or animals in which the small intestine had been extrinsically denervated. In normal animals, submucosal arteries are innervated by extrinsic sensory nerve fibers which contain both substance P and calcitonin gene-related peptide, and by sympathetic noradrenergic nerve fibers. In preparations obtained from animals 5-9 days after denervation, nerve fibers which contained substance P without detectable calcitonin gene-related peptide were associated with a few submucosal arteries. Nerve fibers which contained vasoactive intestinal peptide were also associated with some arteries. By 42-48 days after extrinsic denervation, substance P-containing fibers (without calcitonin gene-related peptide) and vasoactive intestinal peptide-containing fibers were associated with nearly every blood vessel. The extrinsic sympathetic nerve fibers did not regenerate during the course of this study. The nerve fibers associated with submucosal arteries in denervated tissues were not sensitive to capsaicin treatment. The alteration in the innervation of submucosal arterioles that follows extrinsic denervation of the gut may reflect either an increase in the neuropeptide content of the fibers, synthesis of a new peptide, or an increase in the number of fibers as a result of axonal sprouting.

Animals↗
PubMed1992

Increased endocytotic and lysosomal activities in denervated type I and type II muscle fibres.

Previous work has shown that increased endocytotic and lysosomal activities occur in the endplate region of denervated skeletal muscle fibres. This, however, does not engage all fibres of a muscle at a given time after denervation. The present study was carried out in order to determine if both type I (slow) and type II (fast) muscle fibres can react to denervation by increased endocytotic and lysosomal activities. Uptake of horseradish peroxidase as a marker for endocytosis was studied in conjunction with acid phosphatase staining for lysosomal activity in type I and type II fibres of the denervated mouse hemidiaphragm. Fibre typing was performed using a monoclonal antibody against fast skeletal myosin and by adenosine triphosphatase staining. The results show that increased endocytosis and lysosomal activation occur in both type I and type II fibres after denervation.

Acid Phosphatase↗
PubMed1991

Calcium action potentials in innervated and denervated rat muscle fibres.

We studied the generation of calcium action potentials (Ca APs) in innervated and denervated fibres of the extensor digitorum longus of the rat in a tetraethylammonium (TEA) sulphate solution plus 3-4 diaminopiridine (3-4 DAP). The main results are the following: (1) more than 90% of the innervated fibres were capable of developing well-sustained Ca APs that were blocked by Cd or nifedipine; (2) the incidence of Ca APs obtained from the denervated fibres was substantially lower than in the control preparations; (3) no relation was found between the appearance of Ca APs in the denervated fibres and the resting membrane potential (Vm), stimulus duration (500-2000 ms) or holding potential (-80, -100 mV); (4) The percentage of denervated fibres that exhibited Ca APs was increased significantly with the following procedures. First, by raising the external Ca concentration to 14 mM; second, by depleting the intracellular K concentration by overnight exposure of the muscles to a free K-Cs solution; (c) and third, by incubating the muscles in 500 nM apamin, a venom that inhibits the K conductance activated by Ca. Several factors may be involved in the lower incidence of Ca APs obtained in denervated fibres: (1) a diminished Ca current due to a reduction in the driving force as a result of an increment in the intracellular Ca concentration; (2) a persistence of a shunting K conductance that is not inhibited by TEA and 3-4 DAP; (3) a shift in the voltage dependence of the activation and inactivation parameters of the Ca current or the appearance of a new type of Ca channel with a different kinetics.

4-Aminopyridine↗
PubMed1975

Further evidence for a cAMP dependent regulation of tyrosine-3-monoxygenase induction in adrenal medulla: effect of denervation.

Unilateral adrenal denervation caused a gradual decrease of adenylate cyclase activity in rat adrenal medulla. The extent of the increase in adrenal medullary 3',5'-cyclic adenosine monophosphate (cAMP) content elicited by injections of carbamylcholine declined gradually folling adrenal denervation. Three or nine days after denervation carbamylcholine caused rise of cAMP and a delayed increase of tyrosine-3-mono-oxygenase (TH) activity of similar magnitude in intact and denervated adrenal medullae. However, after an interval of 15 days or longer following denervation the increase in TH activity elicited by carbamylcholine was greatly reduced. These results support previous proposals that cAMP is involved as a second messenger in the trans-synaptic induction of TH.

Adenylyl Cyclases↗
PubMed1978

Effect of denervation and ouabain on the response of the resting membrane potential of rat skeletal muscle to potassium.

The effects of denervation and ouabain on the relationship between resting membrane potential (EM) and extracellular potassium concentration were determined for rat soleus (SOL) and extensor digitorum longus (EDL) muscles. At concentrations above 20 mM for both SOL AND EDL fibres the relationship could be described adequately by the Nernst equation. Denervation resulted in reduction of EM and a decrease in the slope of the relationship between EM and potassium concentration. 10(-3) M ouabain produced the same effects as denervation. The results are discussed in relation to the alterations in membrane permeability previously shown to occur as a consequence of denervation. It is concluded that the low EM of denervated muscle is the result of an increase in membrane permeability to sodium.

Animals↗
PubMed1981

Contractures in normal and denervated inferior oblique muscle of the rabbit.

Isometric contracture responses of normal and denervated inferior oblique muscles (IO) of the rabbit have been investigated in vitro at 35 degrees C. The threshold concentration for eliciting potassium contractures was about 20 mM K+. In normal IU low potassium concentrations up to about 50 mM K+ evoked only sustained contractures, higher concentrations were responded by contractures with an initial transient component. The transient tension development was maximal at about 100 mM K+ the sustained component at 80 mM K+. After denervation the characteristic time course of the contractures was not changed, but the tension output of the preparation was diminished and long-term denervated IO have a somewhat lowered threshold. In normal IO acetylcholine (ACh), succinylcholine (SCh) and choline (Ch) caused also sustained contractures, the threshold doses were about 5 microM for ACh and SCh and 500 microM for Ch. The ACh sensitivity of the preparations was increased by physostigmine and decreased or abolished by d-tubocurarine. Denervation increased the drug sensitivity but the shape of the contractures was hardly influenced. The properties of slow tonic muscle fibres in mammalian extraocular muscles (EOM) probably responsible for sustained contractures and their changes after denervation are discussed.

Acetylcholine↗
PubMed1987

Effects of external cations and calcium-channel blockers on depolarization-contraction coupling in denervated rat twitch skeletal muscles.

In the double mannitol gap arrangement the contraction was estimated in single fibres isolated from rat extensor digitorum longus (e.d.l.) muscles that had been denervated for 2-48 days. Denervation induced large changes in the characteristics of the action potential and of the twitch. Up to 15-20 days after denervation the contraction-depolarization curve was sigmoidal and the maximum amplitude of the contraction was not modified by variation of [Ca]o or [Na]o. After 15-20 days of denervation a bell-shaped curve described the relation between contraction and potential. The maximum amplitude was dependent upon the [Ca]o. In Ca-free solution no contractile response was obtained. In Na-free, Ca-containing solution the relationship between contraction and potential was not modified by the addition of divalent cations Co2+, Cd2+, Mn2+, Mg2+, Ni2+, or Ba2+. The contraction, which appeared in Ca-free solution, was restored by adding Sr2+. D600, verapamil and bepridil failed to change the amplitude of the contraction while a marked reduction was found with dihydropyridines. The reduction was overcome by increasing [Ca]o. The present results suggest that the slow calcium current is not involved in the generation of the contractile responses developed by denervated muscles in Na-free (TEA) solution.

Action Potentials↗