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PubMed1984

Effects of denervation and axotomy on nervous system-specific protein, ornithine decarboxylase, and other enzyme activities in the superior cervical sympathetic ganglion of the rat.

The time courses of changes of three enolase isozymes (alpha alpha, alpha gamma, and gamma gamma), S-100 protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), ornithine decarboxylase (ODC), beta-galactosidase, and glucose-6-phosphate dehydrogenase (G6PDH) were examined from 1 to 14 days after cutting of the preganglionic nerve (denervation) or the postganglionic nerve (axotomy) of the superior cervical sympathetic ganglion (SCG) of the rat. The wet weight and protein content in the axotomized SCG increased continuously, to nearly twice those of the denervated SCG for 1-2 weeks after the operations. Among enolase isozymes in the SCG, neuron-specific gamma gamma-enolase decreased rapidly after denervation and stayed at a low level for 2 weeks, whereas the isozyme remained almost unchanged after axotomy. On the contrary, ganglionic alpha alpha-enolase and the alpha gamma-hybrid form increased remarkably to reach a maximum at the second day after axotomy, and remained above control for 1 to 2 weeks; these two enolase isozymes showed little change after denervation. Denervation caused a much larger increase than did axotomy in the ganglionic S-100 protein, an astrocyte-specific protein, during the first week after the operation, while the protein content decreased after 2 weeks of either denervation or axotomy. CNPase, a myelin-associated enzyme, rose suddenly 2 days after axotomy, and remained at a rather high level compared with the denervated ganglion, which showed little variation.(ABSTRACT TRUNCATED AT 250 WORDS)

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1990

Effects of electrical stimulation on molecular forms of butyrylcholinesterase in denervated fast and slow latissimus dorsi muscles of newly hatched chicken.

The effects of denervation and direct electrical stimulation upon the activity and the molecular form distribution of butyrylcholinesterase (BuChE) were studied in fast-twitch posterior latissimus dorsi (PLD) and in slow-tonic anterior latissimus dorsi (ALD) muscles of newly hatched chicken. In PLD muscle, denervation performed at day 2 substantially reduced the rate of rapid decrease of BuChE specific activity which takes place during normal development, whereas in the case of ALD muscle little change was observed. Moreover, the asymmetric forms which were dramatically reduced in denervated PLD muscle were virtually absent in denervated ALD muscle at day 14. Denervated PLD and ALD muscles were stimulated from day 4 to day 14 of age. Two patterns of stimulation were applied, either 5-Hz frequency (slow rhythm) or 40-Hz frequency (fast rhythm). Both patterns of stimulation provided the same number of impulses per day (about 61,000). In PLD muscle, electrical stimulation almost totally prevented the postdenervation loss in asymmetric forms and led to a decrease in BuChE specific activity. In ALD muscle, electrical stimulation partially prevented the asymmetric form loss which occurs after denervation. This study emphasizes the role of evoked muscle activity in the regulation of BuChE asymmetric forms in the fast PLD muscle and the differential response of denervated slow and fast muscles to electrical stimulation.

Animals↗
PubMed1961

Effects of drugs on partially and completely denervated skeletal muscle of the frog.

The sensitivity of completely denervated and the innervated end-plate regions of partially denervated frog's sartorius muscles to stimulation by drugs has been investigated. The drugs were tested on muscles isolated 12 to 39 days following denervation. On the basis of the results obtained most of the drugs could be put into one of two main groups. The first group included choline, tetramethylammonium, carbachol and decamethonium; these drugs readily stimulated non-denervated muscles, and chronic denervation, either partial or complete, greatly increased the sensitivity of the muscles. The second group included pilocarpine and carbamate of (2-hydroxypropyl) trimethyl ammonium chloride (Bethanechol, U.S.P.). The muscles were relatively insensitive to stimulation by these two drugs. They could stimulate the muscles if applied in high enough concentrations, but the responses thus obtained could not be distinguished from responses produced by similar concentrations of sucrose and chronic denervation did not increase the sensitivity of the muscles to stimulation by these two drugs. Methacholine, like the drugs in the second group, was unable to stimulate the muscles in low concentrations, but chronic denervation rendered the muscles sensitive to stimulation by this drug. Tetraethylammonium presented a completely different pattern of activity which was consistent with a hypothesis that in low doses this drug stimulates skeletal muscle by causing a release of acetylcholine from nerve endings in the muscle.

Acetylcholine↗
PubMed2005

Determination of the chronaxie and rheobase of denervated limb muscles in conscious rabbits.

Measurements of the rheobase and chronaxie can be used to define the excitability of nerves and muscles. The aim of this study was to obtain a record over many weeks of changes in the rheobase and chronaxie of denervated rabbit tibialis anterior muscle (TA). A custom-built electronic stimulator was implanted into the peritoneal cavity of New Zealand White rabbits. Large stainless steel electrodes were placed on the denervated TA muscle. Rheobase and chronaxie were measured noninvasively at weekly intervals by means of a laptop PC, which communicated with the stimulator via a radio-frequency link. At each setting the denervated TA was palpated manually to detect the response of the muscle. During the first few days after denervation the rheobase increased transiently to 0.8 +/- 0.13 mA, approximately twice the value for normal innervated muscle, then decreased to normal for the remainder of the experimental period. Chronaxie underwent a significant 3-fold increase from 4.5 +/- 1.1 ms to 14.1 +/- 1.1 ms during the first two weeks of denervation and remained elevated throughout. The custom-built implantable electronic stimulator allowed changes in muscle excitability to be studied over a long period of denervation within individual animals, providing an accurate assessment of the time course of denervation-induced changes in muscle excitability.

Analysis of Variance↗
PubMedDate not supplied

Timing the commitment to a wound-healing response of denervated limb stumps in the adult newt, Notophthalmus viridescens.

Adult newt limbs that are denervated 1 day after amputation undergo a wound-healing response and, although they become reinnervated, will not regenerate unless reinjured. Experiments were designed to determine when denervated limb stumps of adult newts become committed to a wound-healing response. In Experiment I, limbs were amputated and denervated 1 day after amputation. On days 7, 14, 21, 28, and 35 days after the initial amputation and denervation, stumps were reamputated to remove the distal tip. This design varied the time the distal stump was devoid of nerves before reamputation. None of the limbs reamputated at 7 days regenerated. About half of the limbs reamputated at 14 days regenerated and almost all of those reamputated at days 21, 28, and 35 regenerated. In Experiment II, limbs were denervated and then amputated on day 7 or 14, at two different levels. Limbs with a short stump became innervated earlier and regeneration occurred more frequently at both levels of amputation. The results of these experiments show that denervated limb stumps become committed to a wound-healing response between days 7 and 14 after amputation/denervation. If sufficient nerves arrive before day 7, a regeneration response is initiated. If the stump is denervated for 14 days or longer, commitment to wound healing occurs and ingrowing nerves cannot initiate a regeneration response.

Amputation Stumps↗
PubMed1980

Alterations in membrane electrical properties during long-term denervation of rat skeletal muscles.

Some membrane electrical properties of the extensor digitorum longus muscle of the rat were examined up to 21 days after denervation. The resting potential was significantly more depolarized at 3 days after denervation than it was at later times. The rate of rise (dV/dt) of the action potential decreased throughout the time course of the study but approached a steady value between 14 and 21 days after denervation. In addition, the dV/dt of tetrodotoxin (TTX)-resistant action potentials increased up to and including 7 days after nerve section, but declined thereafter. When expressed as % of control, the dose-response to TTX was similar throughout denervation. It is suggested that the large depolarization observed early in denervation may be related to the turnover of membrane constituents occurring at this time. The results also suggest that denervation produces a reduction in the number of fast TTX-sensitive Na+ channels with the appearance of a new population of slow TTX-resistant channels. However, long term denervation results in a reduction in the density of both types of channels.

Action Potentials↗
PubMed1987

Reflex changes in sympathetic nerve activity during mechanical ventilation with PEEP in sino-aortic denervated rats.

The aim of this study was to evaluate the role of cardiopulmonary receptors with vagal afferents in the reflex control of sympathetic nerve activity during mechanical ventilation with positive end-expiratory pressure (PEEP). Experiments were performed on 17 chloralose-anaesthetized rats. Changes in renal sympathetic nerve activity (RSNA), heart rate and mean arterial pressure were studied at zero end-expiratory pressure (ZEEP) and at 5 and 10 cm H2O PEEP in intact animals (n = 8), after sino-aortic denervation (n = 17) and after sino-aortic denervation plus vagotomy (n = 10). In the intact animals, 10 cm H2O PEEP induced a significant increase in RSNA (+66%) and heart rate (+10%) while the mean arterial pressure did not change significantly. Sino-aortic denervation increased baseline levels of RSNA, heart rate and mean arterial pressure. After sino-aortic denervation, 10 cm H2O PEEP still induced a significant increase in RSNA (+22%) and heart rate in 13 animals. In four animals, 10 cm H2O PEEP elicited a depressor reflex with a significant decrease in both RSNA (-32%) and heart rate. Bilateral vagotomy after sino-aortic denervation at ZEEP significantly increased RNSA (+15%) and heart rate, indicating an ongoing tonic inhibitory influence on RSNA from vagal afferents in sino-aortic denervated rats. The PEEP did not induce any significant change in RSNA or heart rate after sino-aortic denervation plus vagotomy. The results indicate that cardiopulmonary receptors with vagal afferents contribute to the reflex excitation of the sympathetic nervous system during mechanical ventilation with PEEP. Under certain circumstances, PEEP may also trigger powerful depressor reflexes, mediated by vagal afferents.

Animals↗
PubMed2006

Upregulation of gene encoding adipogenic transcriptional factors C/EBPalpha and PPARgamma2 in denervated muscle.

Muscle denervation induces fatty degeneration in skeletal muscle. However, the possible mechanism(s) remains to be elucidated. To gain insight into the regulation of this process, this study was designed to characterize the expression pattern of genes encoding transcriptional factors that regulate adipogenesis and the terminal differentiation marker of adipocytes in denervated muscle. Female mice underwent surgery to transect the sciatic nerve, and then the gastrocnemius muscles were harvested 5, 10, 20 or 30 days after surgery. The extent of fatty degeneration was assessed as lipid accumulation by Oil Red O staining. The cellular localization of CCCAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma2 (PPARgamma2), which play an important role in the regulation of adipocyte differentiation, was assessed by immunohistochemistry. The mRNA levels were analysed using a real-time polymerase chain reaction. After muscle denervation, most muscle fibres atrophied pathologically, and lipid accumulation was observed in the superficial region of the gastrocnemius muscle, suggesting that fatty degeneration occurs in this model. Both C/EBPalpha and PPARgamma2 proteins were observed in the interstitial space of denervated muscle but detected in small amounts in normal muscle. The expression levels of C/EBPalpha and PPARgamma2 were significantly upregulated 30 days after muscle denervation. The expression levels of fatty acid binding protein 4 (FABP4), which reflects fatty acid metabolism, were decreased slightly at 5 and 10 days and then returned to control levels 30 days after muscle denervation. These findings suggest that muscle denervation-induced fatty degeneration may be mediated through C/EBPalpha and PPARgamma2.

Adipogenesis↗
PubMed1974

Dynamic properties of denervated fast and slow twitch muscle of the cat.

1. Isometric and isotonic contractions were recorded from cat flexor digitorum longus (FDL) and soleus muscles denervated for 28-35 days and compared with the responses of contralateral control muscles.2. Isometric twitch time to peak was longer in the denervated muscles than in the controls. Tetanic tension was reduced whether expressed as absolute units, per gram or per unit area. Absolute twitch tensions were reduced less below the control values with a consequent increase of twitch-tetanus ratio. These results agree with earlier reports; but, in contrast, there was no reduction in the relative rate of rise of tension in the isometric tetanus of denervated compared with control FDL. The maximum rate of rise of tension in the twitch was only a little less than that in the fully fused tetanus in the denervated muscles.3. Whole muscle shortening velocity was reduced in the denervated soleus with no change in the number of sarcomeres per fibre. There was a smaller change in FDL muscles. This was the result of an increase in the number of sarcomeres per fibre which followed denervation in FDL, compensating for a decreased velocity of shortening of the sarcomere. Maximum sarcomere shortening velocity was reduced by 30% relative to control values in both muscles.4. Measurements were made of the isometric contractions resulting from pairs of stimuli in an attempt to assess the period of maximal activation in the twitch. Maximum summation occurred when the second stimulus was given close to the time of the peak of the twitch in the denervated muscles.

Animals↗
PubMed1974

The binding of tetrodotoxin and alpha-bungarotoxin to normal and denervated mammalian muscle.

1. The binding of [(3)H]tetrodotoxin and [(125)I]iodo-alpha-bungarotoxin to innervated and denervated rat diaphragm muscle has been measured.2. A saturable component of tetrodotoxin binding, which was inhibited by saxitoxin, was detected in addition to considerable non-saturable binding. The saturable component had an equilibrium constant of K = 6.1 nM (limits 4.7-7.8 nM) and binding capacity M = 2.5 f-mole/mg wet wt. (limits 2.1-2.8 f-mole/mg).3. If the saturable component consisted of one-to-one binding of tetrodotoxin to sodium channels, the density of sodium channels would be about 21/mum(2) of surface membrane, a figure similar to that found in other excitable membranes.4. After denervation the specific tetrodotoxin binding, as measured by the ratio M/K, fell by a factor of 2.8. This change appeared to be due to a fall in binding capacity rather than a decrease in affinity.5. After denervation the maximum rate of rise of the action potential fell by 27% and became partially resistant to tetrodotoxin. The maximum rate of rise was at first reduced by tetrodotoxin in similar concentrations to those affecting normal muscle, but even large concentrations which completely blocked normal muscle only reduced the maximum rate of rise by a factor of about 2.6. Detubulation with glycerol did not appreciably affect the tetrodotoxin sensitivity of normal or denervated muscle.7. Tetrodotoxin resistance was not observed after denervation of the frog sartorius muscle.8. [(125)I]iodo-alpha-bungarotoxin binding amounted to 3.8 +/- 0.7 f-mole/mg in innervated muscle and 44.5 +/- 2.1 f-mole/mg in denervated muscle. Most of the uptake was inhibitable by (+)-tubocurarine.9. The increase in the labelled bungarotoxin binding is much larger than the specific tetrodotoxin binding of innervated muscle, which renders implausible the possibility that the acetylcholine receptors which appear after denervation are related to the tetrodotoxin resistant-sodium channels.

Action Potentials↗
PubMed1977

Changes produced by chronic denervation in the temperature-dependent isometric contractile characteristics of rat fast and slow twitch skeletal muscles.

1. Influence of temperature (range 20-35 degrees C) on the isometric contractile properties of normal and chronically denervated fast-twitch extensor digitorum longus and slow-twitch soleus muscles of the rat have been studied in vitro. 2. The times to peak twitch tension of denervated muscles were longer than those of normal in both types of muscle. The denervated muscles were, however, identifiable as 'fast-twitch' or 'slow-twitch' throughout the entire temperature range. 3. The twitch tension/tetanic tension ratios of the denervated muscles at 35 degrees C were significantly higher than those of the normal muscles. 4. The twitch tension of the normal extensor digitorum longus muscles increased whereas that of the normal soleus muscles decreased with cooling from 35 to 20 degrees C. Such a qualitative difference did not exist between the denervated extensor digitorum longus and soleus muscles. The twitch tensions of both denervated muscles decreased with cooling. 5. Cooling to 20 degrees C resulted in a greater fall in tetanic tension in the denervated than in the normal muscles.

Action Potentials↗
PubMed1979

The effects of renal denervation and meclofenamate on renal blood flow regulation in conscious rabbits.

1. The effect on renal blood flow regulation of unilateral renal denervation followed by administration of a prostaglandin synthesis inhibitor has been studied in nine conscious rabbits.2. Renal blood flow distribution was estimated using radioactive microspheres injected via a pre-implanted left ventricular cannula. Cardiac output was estimated by thermodilution. Measurements were made before and after intravenous injection of Meclofenamate, Parke Davis Ltd (4 mg/kg).3. Renal denervation caused a fall in renal cortical catecholamine concentration of approximately 50% by 48 hr.4. Resting renal blood flow did not differ significantly between denervated and innervated kidneys.5. Meclofenamate caused a significant rise in arterial pressure from a mean of 59 to 70 mmHg. In innervated kidneys, Meclofenamate caused a fall in renal blood flow from 8.1 +/- 0.6 (mean +/- S.E. of mean) to 6.5 +/- 0.4 ml./min.g kidney weight while in denervated kidneys it caused a fall from 8.9 +/- 0.7 to 6.25 +/- 0.3 ml./min.g. After Meclofenamate flow was redistributed away from the inner cortex in the innervated kidney and paradoxically towards the inner cortex in the denervated one.6. It was concluded that in conscious animals, resting sympathetic tone has little effect on renal blood flow. The exaggerated reduction in flow in the outer cortex of the denervated kidney following Meclofenamate may indicate denervation hypersensitivity to circulating catecholamines unmasked by reduced synthesis of vasodilator prostaglandins. Alternatively, renal sympathetic nerves may normally prime prostaglandin synthesis in the outer cortex.

Animals↗
PubMed1981

The effects of denervation on contractile properties or rat skeletal muscle.

1. Isometric contractions of fast and slow twitch muscles of rats were recorded 1-42 days after denervation. 2. The major changes occurred over the period from 2 to 6 days after denervation. These changes were qualitatively similar in the two types of muscle. The most important effects were on the twitch: times to peak and half relaxation were prolonged, active tension and peak rate of rise of tension were increased. Tetanic tension per unit cross-sectional area and the maximum rate of rise of tension decreased during this period but, in the second week, the tension recovered substantially and the maximum rate recovered completely. 3. Very small differences were seen between muscles denervated with short and long nerve stumps at day 4. 4. In the late stage of denervation (7-42 days) twitch and tetanic tension fell more than cross-sectional area, but this may have been due to greater atrophy of fibres compared with other muscle tissue. 5. Apart from this tension fall, there were only small changes in the fast muscle in the late stage of denervation. These were a fall in twitch-tetanus ratio and a prolongation of relaxation. 6. In more than half of the soleus muscles there was a late reversal of some of the denervation changes, and these muscles showed a greater degree of atrophy. The less atrophied soleus muscles maintained a prolonged twitch and a low rate of development of tension. 7. It is concluded that denervation affects the contractile properties of muscle as early and as abruptly as it does the membrane properties, and that most of the contractile changes are a direct consequence of changes in excitation-contraction coupling alone.

Animals↗
PubMed1983

The regulation of extrajunctional acetylcholine receptors in the denervated rat diaphragm muscle in culture.

The regulation of the number of extrajunctional acetylcholine (ACh) receptors was assayed by 125I-labelled alpha-bungarotoxin binding sites in denervated rat diaphragm muscle in culture. Sustained K depolarization does not eliminate extrajunctional ACh receptors. In fact, muscle cultured in high-K medium (normal Cl) for 3 days exhibits a greater binding capacity than controls. Under conditions in which the intracellular Cl concentration is unaltered (high-K-low-Cl medium) this effect of high-K medium on the number of extra-junctional ACh receptors is blocked. The number of extrajunctional receptors increases 24-48 h after exposure to high-K-normal Cl medium, similar to the time course of the initial appearance of extrajunctional receptors in the denervated diaphragm muscle in vivo or in organ culture in normal media. High-K-normal Cl medium did not alter the rate of receptor degradation. Electrical stimulation of denervated muscle strips cultured in low-Ca medium containing D-600 eliminated extrajunctional receptors as efficiently as stimulation of muscles in control medium. Electrical stimulation did not reduce the extrajunctional ACh receptor population in glycerol-treated uncoupled muscles to the same extent as in untreated muscles. The extrajunctional ACh receptor content of denervated muscle cultured for 3 days in 2 and 5 mM-caffeine was reduced by about half respectively. Denervated muscle cultured in 0.3 mM-caffeine did not differ from control denervated muscle. Other agents which may alter intracellular cyclic nucleotide levels: dibutyryl cyclic GMP, dibutyryl cyclic AMP, papaverine, and sodium nitroprusside, did not mimic the effect of caffeine or electrical stimulation in lowering the levels of extrajunctional ACh receptors. We conclude that intracellular Ca release from the sarcoplasmic reticulum is necessary for the elimination of extrajunctional ACh receptors in denervated muscle. The levels of intracellular Cl also influence the population of extrajunctional receptors. Conditions which lead to higher levels of intracellular Cl result in greater rates of synthesis of ACh receptors.

Action Potentials↗
PubMed1983

Effects of denervation on sodium, potassium and [3H]ouabain binding in muscles of normal and potassium-depleted rats.

K depletion leads to a selective loss of K from skeletal muscles, which is associated with a decrease in the number of [3H]ouabain binding sites. The significance of the nerve supply for these changes has been assessed in denervation experiments with K-depleted rats. In K-depleted rats (age 4-12 weeks) denervation led to a partial recovery of the K contents in soleus (46-77%), gastrocnemius (23%) and extensor digitorum longus (e.d.l.) muscles (19%) within 24 h. These effects were not prevented by beta-adrenoceptor blockade or mimicked by alpha-adrenoceptor blockade. In K-depleted rats the number of [3H]ouabain binding sites was not increased following denervation. In K-depleted rats 24 h of plaster immobilization of the entire hind limb caused 51% recovery of the total K content in soleus, whereas gastrocnemius and e.d.l. showed 49 and 16% recovery, respectively. Tenotomy for 3 h caused a rise in total K content of 33% in soleus muscles from K-depleted rats. Anaesthesia for 3 h increased the total K content by 23%. The recovery of K induced by denervation, immobilization in plaster, tenotomy or anaesthesia was associated with an equivalent decrease in Na content. Denervation performed before K depletion reduced the loss of K from soleus, but not from gastrocnemius and e.d.l. In both soleus and e.d.l. the number of [3H]ouabain binding sites, however, decreased to the same level as in the contralateral innervated muscles. Denervation reduced, but did not prevent, the increase in the number of [3H]ouabain binding sites seen after re-administration of K to K-depleted rats. It is concluded that the changes in Na-K contents seen after denervation in K-depleted rats are the outcome of cessation of muscle activity. The results give no support to the idea that the effects of K depletion on the K content and the number of [3H]ouabain binding sites in skeletal muscle are mediated by the peripheral nerves.

Animals↗
PubMed1991

Effects of chronic electrical stimulation on contractile properties of long-term denervated rat skeletal muscle.

1. The contractile properties of fast-twitch (extensor digitorum longus or EDL) and slow-twitch (soleus) muscles in the rat were followed for periods of between 4 and 10 months after denervation. The effects of chronic electrical stimulation during the last 3-8 weeks of denervation were investigated. 2. The fall in tetanic tension that follows axotomy ended after about 4 months' denervation. The equilibrium tension was about 0.75% of control tension in EDL and 0.2-0.3% in soleus. 3. The low tension in soleus was due partly to the small diameter of the muscle fibres (atrophy) and partly to their necrosis that resulted in an 8-fold fall in specific tension (the force per unit cross-sectional area). Similar but less extreme changes occurred in EDL. 4. It is speculated that the final level of tension reached by unstimulated denervated muscles is an equilibrium between decrease in force due to atrophy and necrosis and increase due to regeneration. Differences between the final tension levels in soleus and EDL cannot be accounted for quantitatively by known differences in atrophy alone. Therefore, the rate of necrosis in soleus and of regeneration in EDL may be higher. 5. Chronic stimulation of long-term denervated muscle increased force generation by about 7-fold in EDL and between 20 and 55 times in soleus. The final tension reached was between 4 and 5% of normal in both muscles. Specific tension of fibres was almost completely restored by stimulation and the number of fibres was normal. The failure to recover full tension was largely due to failure to reverse denervation atrophy completely. 6. Twitch contraction and relaxation times were identical in denervated-stimulated soleus and EDL. There was no evidence for dependence on duration of stimulation or tension of the muscle. The normalized maximum rate of rise of tetanic tension remained higher in EDL than soleus.

Animals↗
PubMed2006

Muscle denervation promotes opening of the permeability transition pore and increases the expression of cyclophilin D.

Loss of neural input to skeletal muscle fibres induces atrophy and degeneration with evidence of mitochondria-mediated cell death. However, the effect of denervation on the permeability transition pore (PTP), a mitochondrial protein complex implicated in cell death, is uncertain. In the present study, the impact of 21 days of denervation on the sensitivity of the PTP to Ca2+-induced opening was studied in isolated muscle mitochondria. Muscle denervation increased the sensitivity to Ca2+-induced opening of the PTP, as indicated by a significant decrease in calcium retention capacity (CRC: 111 +/- 12 versus 475 +/- 33 nmol (mg protein)(-1) for denervated and sham, respectively). This phenomenon was partly attributable to in vivo mitochondrial and whole muscle Ca2+ overload. Cyclosporin A, which inhibits PTP opening by binding to cyclophilin D (CypD), was significantly more potent in mitochondria from denervated muscle and restored CRC to the level observed in mitochondria from sham-operated muscles. In contrast, the CypD independent inhibitor trifluoperazine was equally effective at inhibiting PTP opening in sham and denervated animals and did not correct the difference in CRC between groups. This phenomenon was associated with a significant increase in the content of the PTP regulating protein CypD relative to several mitochondrial marker proteins. Together, these results indicate that Ca2+ overload in vivo and an altered expression of CypD could predispose mitochondria to permeability transition in denervated muscles.

Animals↗
PubMed1994

Renal perfusion pressure and renin secretion in bilaterally renal denervated sheep.

To further investigate the influence of renal nerves on renin secretion, the renin secretion responses to step reductions of renal perfusion pressure (RPP) were studied in conscious sheep with innervated kidneys (n = 5) and with bilaterally denervated kidneys (n = 5). The average basal level of RPP in sheep with denervated kidneys (82 +/- 4 mmHg; 1 mmHg = 133.3 Pa) was similar to that in sheep with innervated kidneys (83 +/- 3 mmHg). RPP was reduced in four sequential 15-min steps, to a final level of 54 +/- 2 mmHg in sheep with innervated kidneys and to 57 +/- 1 mmHg in denervated sheep. The renin secretion rate was increased as RPP was reduced in sheep with innervated kidneys. Baseline peripheral plasma renin activity was reduced and there was almost no response of renin secretion rate to reduction of RPP in sheep with denervated kidneys. Also, baseline renal blood flow, urine flow rate, sodium excretion rate, and potassium excretion rate were higher in sheep with denervated kidneys than those with innervated kidneys. Baseline plasma angiotensin II was similar in both groups of sheep. As RPP was decreased, plasma angiotensin II was increased in sheep with innervated kidneys, but was not RPP or renal denervation. In conclusion, hormonal factors, such as angiotensin II and atrial natriuretic factor, do not account for the dramatic suppression of renin secretion in response to the reduction of RPP in sheep with bilateral renal denervation. Renal nerves are a necessary component in the control of renin secretion during reduction of RPP and may contribute to the regulation of baseline plasma renin activity and sodium excretion rate in conscious ewes.

Angiotensin II↗