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Of post-denervation hypertrophy in chick slow muscle fibres after complete elimination of stretch and tension.

For the slow muscle fibres in the pure slow muscle ALD as well as in two mixed muscles, flexor metacarpi ulnaris and sartorius, it is demonstrated that the phenomenon of post-denervation hypertrophy still occurs under conditions preventing stretch of muscle after denervation or even in tenotomized muscles in shortened state relieved of tension. Striking differences between the slow fibres of the ALD and those of the mixed muscles are seen, both with respect to their histochemical property and to the degree of development of post-denervation hypertrophy. The slow fibres in mixed muscles show the phenomenon of post-denervation hypertrophy in a much more striking form than do the ALD fibres, and should be used in further studies of the phenomenon.

Animals↗

Regional differences in the effects of denervation, cocaine and chronic reserpine administration on the responses of the rat vas deferens to norepinephrine and acetylcholine.

The prostatic half and epididymal half of the rat vas deferens was found to show the difference with respect to both the sensitivity (expressed as the geometric mean ED50) and maximal response to norepinephrine and acetylcholine. The epididymal half was more sensitive to both drugs than the prostatic half; the maximal response to norepinephrine was greater in the epididymal half than in the prostatic half. Effects of denervation, 10-6 M cocaine and chronic administration of reserpine (1 mg/kg/day for 5 days) on the responses to the drugs were also found to be qualitatively and/or quantitatively different between the two halves. In the epididymal half, all these procedures produced supersensitivity to acetylcholine as well as to norepinephrine. Whereas, in the prostatic half, supersensitivity to only norepinephrine was observed; the responses to acetylcholine were more or less depressed, accompanied by little change in the sensitivity, by these procedures. Degree of supersensitivity (ED50 control/ED50 treated) to norepinephrine produced by denervation was greater in the prostatic half than in the epididymal half. However, in the case of cocaine or reserpine, there was little difference in the degrees of the two halves. In both halves, the maximal response to norepinephrine was increased by denervation and cocaine, but not by reserpine. The magnitude of such increase in the prostatic half was greater and less, after denervation and cocaine, than that in the epididymal half, respectively. Only cocaine increased the maximal response of the epididymal half to acetylcholine. These results are discussed in relation to those previously obtained using whole vas deferens.

Acetylcholine↗

Canine myocardial beta-adrenergic, muscarinic receptor densities after denervation: a PET study.

UNLABELLED: In an effort to better understand cardiac neurotransmission, PET was serially used in dogs to assess changes in ventricular muscarinic (MR) and beta-adrenergic receptor (beta-AR) densities following chemical or surgical denervation. METHODS: Beta-adrenergic and MR receptor concentrations were studied in beagle dogs nine days after chemical sympathectomy (using the neurotoxin 6-hydroxydopamine) or 3-7 wk and 23-28 wk after surgical intrapericardial denervation. RESULTS: In control dogs (n = 13), global beta-AR and MR concentrations were 32 +/- 4 and 62.2 +/- 10.4 pmole/ml tissue, respectively. Nine days after 6-hydroxytk; 1opamine (n = 8), hemodynamic tests and MIBG scintigraphy demonstrated the destruction of cardiac sympathetic innervation. Beta-adrenergic density increased by 190% (p < 0.001) while MR density remained unchanged. Three to 7 wk after surgery (n = 5), hemodynamic tests and MIBG scintigraphy demonstrated both parasympathetic and sympathetic denervations. Beta-adrenergic density was increased by 219% while MR concentration remained unchanged. Twenty-three to 28 wk after surgery, atrial innervation was restored (hemodynamic tests) while ventricular sympathetic innervation was not (MIBG scintigraphy). Beta-adrenergic density remained high. CONCLUSION: The present study demonstrates the ability of PET to serially assess myocardial receptor concentrations. The absence of change in MR density and the prolonged up-regulation of beta-AR following heart denervation are the main findings of the present study.

3-Iodobenzylguanidine↗

Effect of denervation on neuromuscular transmission and glutamate sensitivity of the locust wing muscle fibers.

Changes in neuromuscular transmission and ultrastructure of synapses taking place after motor nerve cutting during 20 subsequent days were studied on the wing muscle of the locust (muscle 120) using intracellular recording from phasic fibres. The membrane potential (MP) and the excitatory postsynaptic potential (EPSP) showed practically no changes in comparison with the controls through day 8 after denervation. After the development of a neuromuscular transmission block between days 8 and 14, EPSP and miniature EPSP (MEPSP) disappeared, and the MP level somewhat decreased in comparison with controls. MEPSP frequency and amplitude increased in the first days after denervation. The sensitivity to glutaminic acid (Glu) gradually increased after nerve cutting, reached maximum on day 8 and remained at the same level subsequently (threshold concentration 0.003 mmol/l vs 0.3 mmol/l in the control). At the same time, the maximum amplitude of depolarization produced by Glu increased 1.5-2 times but slightly decreased subsequently. Beginning from day 4 after denervation synaptic vesicles began forming separate groups. On day 14 vesicles were grouped in macroconglomerates at a distance from the presynaptic membrane. On day 20 no axon profiles could be detected. The results suggest a similarity of denervation changes in insect wing and leg muscles.

Animals↗

The role of denervation in renal transplantation on renal function in the dog.

The role of denervation in renal transplantation on renal function in the dog was assessed in a controlled study. There was no significant difference between innervated and denervated kidney with regard to effective renal plasma flow, glomerular filtration rate, and urinary potassium excretion. However, urinary sodium excretion was elevated, and a significant increase in urinary bicarbonate excretion was observed in the in situ denervated or autotransplanted kidney compared with the innervated control kidney. Denervation rather than either tubular damage from the transplantation procedure or a decreased glomerular filtration rate probably is responsible in part for the observed posttransplant urinary sodium and bicarbonate loss and its associated metabolic problems.

Animals↗

Bronchial contractions in transplanted lungs. Influence of denervation, acute rejection, and the bronchial epithelium.

The effects of pulmonary denervation and rejection on contractions of bronchial smooth muscle and epithelial modulation of these contractions were studied in dogs after denervation in right lung autotransplantation (n = 6) and acute rejection after right lung allotransplantation (n = 8). Immunosuppression was withdrawn from the latter group after 5 days; rejection developed after 3 additional days. A significant (p < 0.05) increase in mean peak airway pressure occurred with rejection of allotransplanted lungs. Rings cut from third-order bronchi of transplanted and contralateral unoperated (native) lungs in each animal were suspended in organ chambers for the measurement of isometric force. In some rings, the epithelium was removed mechanically. Acetylcholine (cholinergic neurotransmitter), serotonin (platelet-product), histamine (mast cell product), and endothelin-1 (endothelium-derived contracting factor) caused concentration-dependent contractions in all rings. In bronchi from native lungs, rings with epithelium contracted less than those without epithelium. This difference was lost after autotransplantation. The smooth muscle and epithelium were affected differently by autotransplantation. Contractions of rings without epithelium decreased in response to acetylcholine and endothelin-1, whereas contractions of rings with epithelium increased in response to histamine and 5-hydroxytryptamine (p < 0.05). During acute rejection, contractions were the same as those after autotransplantation. Bronchial content of endothelin increased fourfold with rejection. Relaxations to isoproterenol and prostaglandin E2 were similar in both groups. In conclusion, denervation reduced the ability of the smooth muscle to contract. The degree of acute pulmonary rejection seen in this study did not further affect bronchial contractions. Modulation of contractions by the bronchial epithelium was lost with both denervation and rejection.

Acetylcholine↗

Impact of electropolarity treatment on contractile kinetics of gastrocnemius muscle of toad (Bufo melanostictus) during denervation.

The twitch properties of denervated muscle were found to be altered contributing to the derangement in the contractile machinery of the denervated muscle. Cathodal polarity treatment minimized the fluctuations and tried to restore denervated muscle back to normalcy to some extent. The anodal polarity treatment was not able to produce favourable effect. The differential effect of polarity treatment on the contractile kinetics of the denervated muscle is discussed.

Animals↗

The effects of denervation, cocaine, 6-hydroxydopamine and reserpine on the characteristics of drug-induced contractions of the depolarized smooth muscle of the rat and guinea-pig vas deferens.

Previous studies have suggested that postjunctional supersensitivity of the vas deferens is due in part to altered electrophysiological properties, the sensitivity of the muscle being increased to any agonist which initiates contraction by means of depolarizing the cell membrane. Results of the present study indicate that altered electrical properties are not the only postjunctional changes which can account for the enhanced response. Dose-response curves for stimulant agonists were obtained in isolated vasa deferentia which were depolarized by a K-rich, Na-free solution. Chronic denervation resulted in a 2- to 3-fold displacement of the dose-response curve for norepinephrine to the left of control. Cocaine (10-(5)M) did not potentiate the response to norepinephrine of the innervated, depolarized smooth muscle. Supporting the contention that the supersensitivity of the depolarized tissue is postjunctional in nature was the finding that the denervated vas deferens was supersensitive to methoxamine, an agent which is not taken up by the neuronal amine transport system. Pretreatment of rats with reserpine (1.0 mg/kg/day for 5-7 days) also produced supersensitivity of the depolarized vas deferens. The increased maximal response to drugs of the denervated rat vas deferens which is observed in normally polarized tissues is absent in depolarized tissues suggesting that the phenomenon of increased maximum requires the existence of a membrane potential in order to be manifest. The denervated vas deferens, but not the vas deferens from reserpine-pretreated animals, exhibits an increase in the duration of drug-induced contractions. This effect occurs in both normal and depolarizing salt solutions suggesting that the change which leads to this phenomenon differs from those alterations which lead to postjunctional supersensitivity and to the enhanced maximal response.

Animals↗

[The ultrastructure of the neuromuscular synaptic terminal in the frog after denervation].

Ultrastructure of certain myoneural terminals were studied on serial sections on day 3, 5 and 8 after denervation. Ultrastructure of the terminal proximal and distal regions and Schwann cell were studied by means of morphometry and reconstruction of single terminals. On day 3 after denervation Schwann cell is activated in terminal proximal regions more rapidly than in distal ones with contractility in the terminal proximal region being more significant than in distal. On day 5 after denervation changes cover both initial and terminal regions and on day 8 almost all the regions where terminal were placed earlier were occupied with Schwann cell. A suggestion is made that structural changes in the Schwann cell-terminal system are the major contributors to decrease of synaptic discharge in early stages of denervation and appearance of Schwann cell potentials in more late ones.

Animals↗

Acetylcholine receptors in innervated muscles of dystrophic mdx mice degrade as after denervation.

Acetylcholine receptors (AChRs) are present at the top of the postsynaptic membrane of the neuromuscular junction (NMJ) at very high density, possibly anchored to cytoskeletal elements. The present study investigated whether AChR degradation is affected in animals lacking dystrophin, a protein that is an integral part of the cytoskeletal complex and is missing in Duchenne muscular dystrophy. The animal model for Duchenne muscular dystrophy, the mutant mdx mouse, was used to determine whether disruption of the cytoskeleton, caused by the absence of dystrophin, affects AChR degradation. Of the two populations of junctional AChRs, Rs (expressed in innervated adult muscles) and Rr (expressed in embryonic or denervated muscles), only Rs are affected in mdx animals. In innervated mdx soleus, diaphragm, and sternomastoid muscles, the AChRs have an accelerated degradation rate (t1/2 of approximately 3-5 d), similar to that acquired by Rs in control muscles after denervation. The Rs in mdx NMJs do not accelerate further when the muscles are denervated. The absence of dystrophin does not affect the degradation rate of the Rr AChRs (t1/2 of 1 d), which are expressed after denervation in mdx as in control muscles. These results suggest that dystrophin or an intact cytoskeletal complex may be required for neuronal stabilization of Rs receptors at the adult neuromuscular junctions.

Animals↗

Skeletal muscle regeneration during aging and after long-term denervation.

Data accumulated in recent years strongly suggest that the basis for at least part of the muscle atrophy seen in old age is related to the diminution of motor innervation in normal muscle and a decreased effectiveness of reinnervation of regenerating muscle fibers. Thus, attempts to stabilize reverse the decline of the skeletal musculature during aging must take into account both the effects of aging on the peripheral nervous system and the presence of populations of denervated muscle fibers in the aging muscles. Of considerable importance is the question of how long muscle fibers in old animals can remain denervated before they begin to lose their capacity for restoration if they ultimately become reinnervated. The experimental studies reviewed here have shown that normal muscles in old animals are capable of a high degree of restoration as long as their motor nerve supply remains undamaged. After a certain period of time, denervated muscle in young animals steadily loses the capacity to restore or repair itself. To date, so little information is available on the properties of denervated muscle in old animals that meaningful comparisons cannot be made. Ultimately, ensuring that normal or injured muscle in old individuals is supplied by an effective motor innervation may be a real key to the problems of muscle loss in old age, but if such could be provided, it will be important that the old musculature, whether normal or injured, is capable of adequately responding to the innervation.

Aging↗

The denervated cremaster muscle of the guinea-pig as a pharmacological preparation.

The pharmacological responses of both denervated and innervated cremaster muscle preparations from the guinea-pig have been investigated and compared. Acetylcholine (ACh) dose-response curves were obtained in both preparations. The affinity constants for (+)-tubocurarine and for atropine were calculated and indicated that the ACh receptors in both preparations were nicotinic. Histamine dose-response curves could be obtained only in the denervated preparation. The response was unaltered by metiamide, and the affinity constant for mepyramine fitted in with those previously obtained by others on ileum and trachea, indicating that the histamine receptors are H1 in type. Sustained contractions were obtained to adrenaline and noradrenaline but not isoprenaline, with the denervated preparations. Schultz-Dale responses were obtained with denervated muscle in sensitized guinea-pigs. This preparation did not respond to 5-hydroxytryptamine, bradykinin, or the slow-reacting substance of anaphylaxis.

Acetylcholine↗

Radio frequency transmyocardial revascularization enhances angiogenesis and causes myocardial denervation in canine model.

BACKGROUND AND OBJECTIVE: Transmyocardial revascularization (TMR) relieves angina and improves exercise tolerance in patients. Angiogenesis and myocardial denervation have been proposed as factors contributing to these benefits. To test whether radio frequency transmyocardial revascularization (RF-TMR) enhances angiogenesis and causes myocardial denervation. STUDY DESIGN/MATERIALS AND METHODS: RF-TMR channels were created in 12 dogs which survived up to 4 weeks. Bromodeoxyuridine was administered subcutaneously to mark proliferating cells as an assay of angiogenesis. Western blot analysis of tyrosine hydroxylase and blood pressure response to topical bradykinin were used as indices of myocardial denervation. RESULTS: RF-TMR increased local vascularity by an average of 50%, whereas the rate of vascular cell proliferation was tripled over that of the untreated region. Changes in mean arterial pressure with bradykinin and tyrosine hydroxylase content were significantly decreased in RF-TMR regions as compared with normal myocardium in the same hearts. CONCLUSION: RF-TMR enhances angiogenesis and causes myocardial denervation in canine myocardium as with laser TMR.

Animals↗

Neural cell adhesion molecule in normal, denervated, and myopathic human muscle.

The neural cell adhesion molecule (N-CAM) is a cell-surface glycoprotein that may mediate some intercellular adhesive interactions in the nervous system. In adult rat muscle, N-CAM is concentrated near neuromuscular junctions and on satellite cells, but is nearly undetectable in nonsynaptic portions of myofibers. However, N-CAM is abundant throughout myofibers in denervated and regenerating muscles. Using affinity-purified antibodies to N-CAM, we were able to demonstrate a similar distribution and regulation of N-CAM in human muscle. Myofiber N-CAM was not detectable immunohistochemically in any of 10 normal biopsies or in 4 biopsies that were abnormal but showed no evidence of fiber denervation or regeneration. N-CAM was present, however, at end plates, nerves, and satellite cells in normal human muscle. In contrast, myofiber N-CAM was detected in 16 of 16 patients with histological evidence of denervation and in 10 of 10 patients who had myopathy with degenerating/regenerating myofibers. In addition, 2 of 2 histologically nondiagnostic biopsies from patients with amyotrophic lateral sclerosis contained N-CAM-positive myofibers. Immunoblot analysis also detected N-CAM in denervated and myopathic, but not normal, human muscle. These results suggest that N-CAM may play a role in muscle reinnervation or regeneration and that N-CAM immunohistochemistry may complement conventional techniques in the diagnosis of neuromuscular disease.

Antigens, Surface↗

Denervation-induced intraspinal synaptogenesis of calcitonin gene-related peptide containing primary afferent terminals.

The purpose of the present study is to provide evidence that chronic spinal denervation leads to an increase in numbers of synaptic terminals from a specific population of primary afferent fibers. Rats were unilaterally deafferented for 35 days (chronic denervation) by dorsal rhizotomies performed from T2 to T8 and T10 to L5, which isolates or spares the T9 root. The contralateral T9 root was spared by similar surgery 5 days (acute denervation) prior to sacrifice. The survival time on the chronic side presumably allows sprouting of T9 primary afferents to occur, whereas the time on the acute side does not. The terminals were labeled with calcitonin gene-related peptide (CGRP), which is a compound that labels a specific population of primary afferent fibers and terminals, and stereological methods were used to determine the numbers of immunolabeled terminals in laminae I and IIo on the chronic and acute sides of the T9 spinal cord. The findings are that the chronic side had approximately twice as many terminals as the acute side. This difference is statistically significant. These findings are compatible with the hypothesis that chronic denervation leads to synaptogenesis from surviving primary afferent fibers.

Animals↗

Necrosis of capillaries in denervation atrophy of human skeletal muscle.

Gastrocnemius muscles from eight adults with moderate to severe denervation of various causes (excluding vascular diseases), along with biopsy specimens from seven controls, were studies in semithin epoxy resin sections and by electron microscopy. Morphometry showed diminution in the number of capillaries per muscle fiber roughly proportional to the degree of muscle fiber atrophy. The number of capillaries per transverse muscle fiber area tended to increase. By phase microscopy, destroyed capillaries were found in all denervated muscle specimens. Denervated muscle becomes relatively overvascularized, and probably as a result, some capillaries become necrotic. This tends to restore the normal equilibrium between muscle mass and blood supply. The capillary changes of denervation can be distinguished from those in dermatomyositis.

Adult↗

Tissue levels and in vivo release of tachykinins and GABA in striatum and substantia nigra of rat brain after unilateral striatal dopamine denervation.

Brain tissue levels and in vivo release of substance P (SP) and neurokinin A (NKA) and GABA were measured bilaterally in striatum and substantia nigra of the rat, after a unilateral 6-hydroxydopamine lesion of the nigro-striatal dopamine pathway. Sham injected animals served as controls. The dopamine denervation decreased the tissue levels of SP in striatum (-38%) ipsilateral to the lesion and in substantia nigra both ipsi- (-54%) and contralateral (-38%) to the lesion. NKA was not significantly changed in the striatum, but decreased (like SP) in the substantia nigra both ipsi- (-50%) and contralateral (-40%) to the lesion. GABA tissue levels increased in the denervated striatum (+20%) and remained unchanged in substantia nigra at both sides. The extracellular levels of SP, NKA and GABA were measured with microdialysis in vivo at basal conditions and during stimulation with potassium administered locally via the microdialysis probe. The stimulated release of SP and NKA in the substantia nigra ipsilateral to the lesion was compared to in sham operated animals reduced with 39% and 64%, respectively, while no change in SP or NKA release was detected in the striatum. The basal release of GABA in the striatum was increased with 296% and with 76% during stimulation in the dopamine denervated striatum, while no change in GABA basal or stimulated release was detected in the substantia nigra. We suggest that the increased GABA release in the dopamine denervated striatum may be due to a decreased dopamine mediated inhibition of local GABA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Cardiac sympathetic denervation does not change the load dependence of the left ventricular end-systolic pressure/volume relationship in dogs.

It has been shown that in the intact canine heart the left-ventricular end-systolic pressure/volume relation (ESPVR) depends on loading conditions: an increase in arterial vascular resistance causes a leftwards shift and a steeper slope of the ESPVR, suggesting an increased inotropic state. Our purpose was to investigate the possible contribution of the sympathetic nervous system to this load sensitivity of the ESPVR, using intact, but denervated, hearts with normal coronary perfusion and afterload. We used two types of loading intervention: venous volume infusion and gradual occlusion of the descending aorta. ESPVRs were obtained in six anaesthetized open-chest dogs, both before and after bilateral ablation of the stellate ganglia. To exclude the influence of heart rate changes, bilateral vagotomy was performed and the heart was paced. The absence of (unpaced) heart rate changes in response to pressure alterations was used to confirm total denervation. Left ventricular pressure was measured with a micromanometer and volume with a conductance catheter. ESPVRs were essentially linear and characterized by their slope (Ees) and volume intercept at 12 kPa (V12). We found that Ees (P < 0.0001) and V12 (P < 0.05) were both significantly different during pressure and volume interventions (0.67 +/- 0.29 and 0.41 +/- 0.18 kPa/ml for Ees and 16.2 +/- 8.2 and 18.2 +/- 8.4 ml for V12 respectively). Denervation did not significantly affect the parameters of the ESPVR obtained by either volume infusion or aortic occlusion. Two-way analysis of variance revealed no significant interactive effect between denervation and intervention, indicating that the sympathetic nervous system does not influence the load dependency of the ESPVR.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗