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Response of normal, denervated, and reserpine-treated arteries to sympathomimetic amines and nicotine in dogs.

The sensitivity of normal, denervated carotid arterial segments, and of carotid arteries of dogs previously treated with reserpine, to sympathomimetic amines and nicotine has been compared using isolated perfused segments of these vessels. Arteries from animals and arterial segments treated with reserpine, denervated by peri-arterial stripping or by re-anastomosing of segments removed and reversed, both showed an increased sensitivity to noradrenaline which correlated well with a decrease in tissue noradrenaline content. Tyramine did not produce vasoconstriction in denervated vessels, but some constriction was observed when the vessels had been pretreated with noradrenaline or with dopamine or dopa. The effect of nicotine upon dog carotid arterial segments was recorded 130 times. The most frequent response was vasodilatation. This involved both the arterial wall per se and the vasa vasorum. The vasodilatation in response to nicotine was seen in arteries from normal and reserpine-treated animals and in denervated vessels.

Animals↗

Effect of sympathetic denervation on chronic cold injuries in rabbit brain. A microangiographical and histological study.

Sympathetic denervation of the brain vessels was performed uni- or bilaterally in 13 adult rabbits, and cortical cold lesions were induced bilaterally 10-18 days afterwards. After a further 4-35 days the vascular and morphological changes in the lesion areas were studied histologically and with angiography. No difference was observed between the denervated and the non-denervated lesion areas. The results are discussed with regard to a proposed functional plasticity of the chronically denervated brain vessels and/or to possible changes in metabolic demands of the brain tissue.

Angiography↗

Changes in monoamine oxidase and catechol-0-methyl transferase activities after denervation of the nictitating membrane of the cat.

1. The question of cellular localizations of monoamine oxidase and catechol-o-methyl transferase, enzymes involved in the metabolism of noradrenaline, has been investigated by following the changes in the enzyme activity of the smooth muscle of the cat nictitating membrane after sympathetic denervation. Any falls in enzyme activity coinciding with the time course for degeneration of the sympathetic nerve endings (2-3 days) can reasonably be ascribed to a former localization of the enzyme within the sympathetic nerve.2. Monoamine oxidase activity of the inferior and medial smooth muscle was significantly reduced 3 days after sympathectomy and remained reduced 14 days after sympathectomy.3. A correlation was found between the fall in monoamine oxidase activity and the endogenous noradrenaline concentration of the contralateral normal muscle, indicating that the higher the endogenous noradrenaline concentration, the greater the fall in monoamine oxidase activity after denervation.4. It was concluded that the fall in monoamine oxidase activity after denervation indicated a former localization of the enzyme within the sympathetic nerve endings.5. The fall in monoamine oxidase activity of the denervated muscle was significantly less measured with benzylamine as a substrate than with tyramine. This suggested that the neuronal monoamine oxidase may have different properties than the extraneuronal enzyme.6. A small fall in the catechol-o-methyl transferase activity of denervated smooth muscle was found and a correlation between the fall in enzyme activity and endogenous noradrenaline indicated that in this smooth muscle a proportion of the catechol-o-methyl transferase activity may be of presynaptic origin.

Amines↗

Anode break excitation in denervated rat skeletal muscle fibres.

1. Anodal break action potentials were found to be a feature of denervated rat skeletal muscle fibres.2. Depolarized innervated fibres failed to respond to anodal break stimulation in the same way as denervated fibres.3. The critical level for action potential generation is related to membrane polarization in denervated fibres but not in innervated fibres. This relationship is inhibited by the I.P. administration of actinomycin D, which also prevents the onset of anodal break action potentials in 3-day denervated fibres.

Journal Article↗

An expanded cortical representation for hand movement after peripheral motor denervation.

OBJECTIVES: Functional reorganisation of the motor or sensory cortex has been demonstrated in animals after section of mixed peripheral nerves. Here functional changes in the motor cortex specifically after peripheral motor denervation in humans are investigated. METHODS: Functional MRI (fMRI) was used to study brain activation during a finger flexion-extension task in patients with a late onset, acquired pure motor neuropathy (n=6), contrasting results with those from patients with pure sensory neuropathies (n=4) or healthy controls (n=7). RESULTS: Increases in the extent of activation in the motor cortex both ipsilateral and contralateral to the hand moved were found in the patients with motor neuropathy. The neuroanatomical localisation of the mixed contralateral sensorimotor cortex activation volume was more posterior for the patients with motor neuropathy than for the healthy controls (mean difference, 12 mm, p<0.05). The pure sensory neuropathy group by contrast showed no change in the extent of activation relative to healthy controls and a trend for more anterior primary sensorimotor cortex activation (p<0.06). To test whether the increased activation volumes found in patients with motor neuropathy were a result simply of factors such as increased effort with movement rather than the motor denervation, patients with hand weakness from inclusion body myositis (n=4) were studied while making similar hand movements. No differences in either the numbers of significantly activated voxels or in their localisation were found relative to healthy controls (n=10). CONCLUSIONS: These results provide a novel demonstration that peripheral denervation (as distinguished from factors related to weakness) leads to functional reorganisation of the sensorimotor cortex in the adult brain. This suggests that adaptive responses to motor denervation involve the central as well as the peripheral nervous system.

Adult↗

Energy balance following sympathetic denervation of brown adipose tissue.

The effects of sham, bilateral surgical denervation or excision of interscapular brown adipose tissue on body composition and energetic efficiency were studied in young CFLP mice kept at 25 degrees C and fed a laboratory stock diet. A preliminary experiment showed that 15 weeks following surgery, total body fat was increased by 42% in the denervated group and by 72% in the excised group while body protein was unchanged. In another 7-week energy balance experiment, body fat was also significantly higher by 15 and 18% in the denervated and excised group, respectively, but metabolizable energy intake was slightly lower than that of sham controls. Determination of energy expenditure both by the comparative carcass slaughter technique and by measurement of daily oxygen consumption showed that the metabolic rate was reduced in the denervated nd excised groups. The capacity for thermogenesis, as measured by an increase in oxygen consumption following injections of noradrenaline (600 micrograms/kg body weight) was similar in energetic efficiency, and indicates an important role of the sympathetic nervous system in the regulation of animal heat production by brown adipose tissue and in the overall control of thermogenesis.

Adipose Tissue, Brown↗

Effects of renal denervation on renin release in response to tilting and furosemide.

In anesthetized cats head-up tilting for 30 min and infusion of furosemide at 0.75 mg/kg in 30 min significantly raised renin release from the innervated kidney (increments of 90.7 +/- 21.4 ng/min on tilting and 105.4 +/- 26.4 ng/min after furosemide); a small and inconstant increase from the contralateral denervated kidney (increments of 16.8 +/- 16.0 and 16.3 +/- 17.7 ng/min, respectively) was abolished by acute bilateral adrenalectomy. Larger doses of furosemide (6.0 mg/kg) could release renin from the denervated kidney also, but the response was still more marked on the innervated side especially in the early period of infusion (increments of 132.7 +/- 23.8 and 33.7 +/- 23.8 ng/min of innervated and denervated sides at 10 min). The response of the denervated kidney to 6.0 mg furosemide/kg was not affected by adrenalectomy. Stimulation of juxtaglomerular cells by tilting is entirely due to sympathoadrenergic activation; stimulation by furosemide is also entirely neural when the diuretic drug is given in moderate doses, but is partly independent of innervation when larger doses are administered.

Adrenalectomy↗

Time course of sympathetic denervation supersensitivity in canine ventricular recovery.

We studied the timing of the electrophysiological effects of sympathetic supersensitivity with chronically implanted electrodes in the anterior and posterior left ventricular free wall in 10 dogs. We produced denervation of the anterior wall in six dogs by application of phenol surrounding the anterior electrode. Drug infusions that were performed under pentobarbital sodium anesthesia included norepinephrine, isoproterenol, and methoxamine. In four controls there was no difference in response of the two sites. Presynaptic supersensitivity was manifest as early as 2 days and as late as 64 days by a parallel left shift (greater than or equal to 8.3 ms) in the norepinephrine dose to effective refractory period shortening response curve in the anterior compared with posterior left ventricle, P less than 0.01. The isoproterenol dose-response curve was also shifted to the left by 5.6 ms (P less than 0.01) but was manifest only after 10 days and only until 28 days from the denervation procedure. Local repolarization in the denervated areas shortened more than the innervated areas with both drugs. The methoxamine dose-response curve was flat, and the anterior-denervated area was not different than the posterior-innervated area. We conclude that recovery properties in ventricular muscle demonstrate evidence of supersensitivity, which is neurotransmitter and beta- but not alpha-receptor specific.

Animals↗

Reserpine but not surgical denervation regulates rat renal beta-adrenergic receptors.

The effects of unilateral surgical denervation or reserpine administration on renal beta-adrenergic receptors were examined in rat kidney cortex. The specific binding of [125I]iodocyanopindolol was used to quantitate the beta-adrenoceptors. Denervation had no significant effect on beta-adrenoceptor concentration in denervated compared with contralateral control kidney, 7 days postsurgery. In contrast, reserpine treatment increased beta-adrenoceptor concentration 30% compared with control (P less than 0.05). Tissue norepinephrine levels were depleted to a significant extent with both manipulations. The reserpine effect was investigated further. Reserpine increased both beta 1- and beta 2-adrenergic receptor subtypes to the same extent. The effect of reserpine was primarily on tubular beta-adrenoceptors including those in the proximal tubules; glomerular beta-adrenoceptors were minimally affected by reserpine. Other adrenergic receptor subtypes (alpha 1- and alpha 2-) were also significantly increased by reserpine; however, angiotensin II receptors were not altered, indicating that the reserpine effect was not a general one affecting all membrane receptors. Reserpine treatment increased beta-adrenergic receptor-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation by 49% over control in the renal cortex. Denervation had no significant effect on cAMP accumulation. Overall, our results suggest that, in addition to sympathetic nerve terminal norepinephrine, other factors may be involved in the regulation of renal beta-adrenergic receptors.

Animals↗

A microsurgical method for denervation of the liver in the rat.

The role of the nerves in the hepato-duodenal ligament should be of special surgical interest, since these nerves are often injured in hepatic and biliary tract surgery. We have developed a microsurgical procedure for liver denervation. All visible nerves were resected after staining. Norepinephrine values in central liver tissue of denervated rats were only 18% of the corresponding values in innervated liver tissue, indicating an appreciable degree of sympathetic denervation. No detectable immunoreactivity of gastrin, cholecystokinin, vasoactive intestinal polypeptide, substance P, somatostatin or enkephalin were found within resected hepatic nerves. The described denervation procedure is simple and reproducible. It can be used to obtain additional information about the nervous regulation of various liver functions.

Animals↗

Sympathetic denervation blocks blood pressure elevation in episodic hypoxia.

We have previously described a rat model that responds to repetitive episodic hypoxia (FiO2 nadir 3-5% for 12 seconds every 30 seconds for 7 hr/day for 35 days) with chronic increase in arterial blood pressure. The purpose of the current study was to determine if peripheral sympathetic nervous system denervation blocks this persistent blood pressure elevation. Chemical sympathetic denervation was achieved and maintained by three intraperitoneal injections (100 mg/kg 6-hydroxydopamine) on days 1, 3, and 27 of a 47-day experiment in two groups of rats. One denervated group was subjected to episodic hypoxia for 40 consecutive days beginning on day 7 and the other remained unhandled in their usual cages. A third group was injected with vehicle only and subjected to the same episodic hypoxia while a fourth group remained unhandled for 40 days. The vehicle-treated, episodic hypoxia-exposed group showed a 7.7 mm Hg increase in mean arterial blood pressure (conscious, unrestrained) over the 40-day period, whereas all other groups showed a decrease in mean arterial pressure. The left ventricle and septum/whole body weight ratio was higher in both episodic hypoxia-exposed groups at the end of the study. Plasma epinephrine in both groups administered 6-hydroxydopamine was higher on day 6 than in the vehicle-injected rats. Measurement of catecholamines in cardiac muscle homogenate confirmed denervation in 6-hydroxydopamine animals. These results indicate that the peripheral sympathetic nervous system is necessary for the persistent increase in blood pressure in response to repetitive episodic hypoxia.

Animals↗

Hypertension following denervation of aortic baroreceptors in unanesthetized dogs.

After cervical aortic nerve section, mean arterial pressure in the unanesthetized dog increased by an average of 7.4 mm Hg. Following a more extensive denervation of aortic arch receptors by section of intrathoracic vagal branches, arterial pressure increased by 16.7 mm Hg. The above changes were seen in the stable state after the effects of surgery had disappeared. In both cases carotid baroreceptors were functional. After administration of nitroglycerin and phenylephrine subsequent to either denervation procedure, blood pressure changes were larger and heart rate responses were smaller than in the control state. The unanesthetized dog regulates mean arterial pressure at a higher-than-normal pressure after aortic baroreceptor denervation. Reflexes from the aortic baroreceptors continuously participate in the normal control of mean arterial pressure. Section of the cervical aortic nerves only partially denervates aortic baroreceptors. Our findings may be relevant to human essential hypertension.

Animals↗

Time course of denervation of efferent sympathetic and vagal nerves after occlusion of the coronary artery in the canine heart.

To determine the time course of efferent sympathetic denervation after transmural myocardial infarction (TMI) and of efferent vagal denervation after transmural or nontransmural myocardial infarction (NTMI), we measured effective refractory periods (ERP) basal and apical to TMI or NTMI in secobarbital-anesthetized, open-chest dogs. In eight dogs with latex-induced TMI, bilateral ansae subclaviae stimulation shortened ERP at all 45 apical and basal test sites before latex injection. After latex injection, ERP shortening was unchanged at all 15 basal sites but was eliminated (less than or equal to 2 msec shortening) at three apical sites in 5-20 minutes and at 14 of 30 apical sites 30-180 minutes after latex injection. At the remaining 13 apical sites, ERP shortening was not eliminated but attenuated significantly in 5-180 minutes. ERP shortening induced by infused norepinephrine (0.20-0.25 microgram/kg/min) did not differ between basal and apical test sites 3-4 hours after latex injection; that is, no supersensitivity occurred. Of six dogs with TMI produced by ligation of multiple coronary arteries without latex injection, ERP shortening induced by efferent sympathetic neural stimulation was eliminated at 10 apical sites in four dogs over a period of 3 hours. At 14 apical sites that did not show denervation in these six dogs, ERP shortening was unchanged. In seven dogs with latex-induced TMI, bilateral vagal stimulation lengthened ERP at all 40 apical and basal test sites before latex injection. Vagally induced ERP lengthening was unchanged at all 13 basal sites after latex injection. ERP lengthening was eliminated (less than or equal to 1 msec lengthening) at four of 27 apical sites in 5-20 minutes and at 13 apical sites 30-180 minutes after latex injection. At the remaining 10 apical sites, ERP lengthening was not eliminated but decreased significantly 3 hours after latex injection. Of nine dogs with ligation-induced NTMI, five dogs showed elimination of vagally induced ERP lengthening at eight apical sites in 3 hours after ligation. ERP lengthening induced by vagal stimulation was unchanged at all 17 basal sites in nine dogs with NTMI. We conclude that TMI produced by latex injection and ligation of multiple coronary arteries produces heterogeneous loss of efferent sympathetic innervation in noninfarcted apical sites as early as 5-20 minutes after coronary occlusion with more complete denervation occurring over time.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Presynaptic modulation of efferent sympathetic and vagal neurotransmission in the canine heart by hypoxia, high K+, low pH, and adenosine. Possible relevance to ischemia-induced denervation.

Ischemia in the dog produces denervation of myocardium apical to the ischemic area. To investigate the mechanism(s) of the denervation, we tested the effects of hypoxia and some components of ischemia including high K+, low pH, and adenosine on efferent cardiac autonomic responses. In anesthetized, open-chest dogs, we occluded a diagonal branch of the left anterior descending coronary artery and perfused it with hypoxic Tyrode's solutions (PO2 less than 50 mm Hg). We found that effective refractory period (ERP) shortening induced by bilateral ansae subclaviae stimulation at myocardium basal and apical to the perfusing area did not change during a 20-25 minute period of perfusion with hypoxic normal Tyrode's solution. During perfusion with hypoxic combined Tyrode's solution containing 12 mM K+, pH 6.8, and 10 microM adenosine, ERP shortening at basal sites induced by bilateral ansae subclaviae stimulation remained unchanged but was attenuated at apical sites (16 +/- 1 to 8 +/- 1 msec, mean +/- SEM, n = 35, p less than 0.001), and seven apical sites exhibited denervation (less than or equal to 2-msec shortening). The maximum extracellular K+ concentration of the perfusing area, measured with a K(+)-sensitive electrode, was 5.1 +/- 0.9 mM (N = 3 dogs) during perfusion with normal Tyrode's solution and was 11.8 +/- 0.1 mM (N = 3 dogs) during perfusion with hypoxic combined solution (p = 0.017). In a separate group of dogs, the effects of high K+, low pH, and adenosine in the absence of ischemia were examined. Oxygenated Tyrode's solutions were instilled into the pericardial cavity to superfuse epicardial nerves. The Tyrode's solutions containing high K+ (12 mM), low pH (6.4), or adenosine (10 microM), individually or combined, reduced ERP shortening induced by bilateral ansae subclaviae stimulation in the ventricular intramyocardium to 46%, 55%, 56%, and 33% of each control value obtained during superfusion with normal Tyrode's solution and reduced the magnitude of ERP lengthening induced by bilateral cervical vagal stimulation to 57%, 71%, 61%, and 39%, respectively. ERP responses of the test sites to infused norepinephrine and methacholine, however, remained unaffected by superfusion with combined Tyrode's solution. Thus, high K+, low pH, and adenosine each inhibit efferent sympathetic and vagal neurotransmission presynaptically in the canine heart and may contribute to the development of denervation during early ischemia.

Adenosine↗

Differential downregulation of beta 2-adrenergic receptors in tissue compartments of rat heart is not altered by sympathetic denervation.

With agonist stimulation, cardiac beta 2-adrenergic receptors (beta 2ARs) are downregulated to a much greater extent than are beta 1ARs. It has been hypothesized that this effect is due to sympathetic innervation inhibiting the downregulation of beta 1ARs. To test this hypothesis, the technique of coverslip autoradiography was used to localize and quantify beta 1AR and beta 2AR subtypes in tissue compartments of the heart in rats subjected to sympathetic denervation by two intravenous injections of 6-hydroxydopamine (50 mg/kg per dose). After denervation, the rats were infused with L-isoproterenol (400 micrograms.kg-1 x h-1 for 7 days) or vehicle (0.001N HCI) by implantation of osmotic minipumps. Sections were incubated with 70 pmol/L of the beta AR antagonist [125I]iodocyanopindolol (ICYP) alone or in the presence of 5 mumol/L DL-propranolol or 5 x 10(-7) mol/L CGP 20712A (a beta 1AR antagonist). Binding of ICYP to sections of rat hearts was saturable and stereoselective and was displaced by beta AR agonists with the rank order of potency expected for beta ARs. There was an 89% reduction in catecholamine concentration in rat ventricles after 1 week of 6-hydroxydopamine treatment, before implantation of the minipumps. Chronic infusion of isoproterenol induced significant downregulation (63% to 74%) of beta 2ARs in atrial and ventricular myocytes, coronary arterioles, and connective tissue but no change in beta 1ARs in these regions in rats with intact sympathetic innervation. Similar changes were seen in denervated animals. There was a marked reduction in beta 2ARs but small insignificant decreases in beta 1ARs, despite the fact that in the denervated animals there was upregulation of beta 1ARs in atrial and ventricular myocytes (approximately 25%). Our study suggests that beta 1ARs in the heart are not significantly downregulated by chronic agonist exposure and that this is unrelated to sympathetic innervation. The underlying mechanism of preferential regulation of beta AR subtypes remains to be elucidated but may be related to differences in the molecular structure between beta 1ARs and beta 2ARs.

Animals↗

Cardiovascular responses to hypoxemia in sinoaortic-denervated fetal sheep.

Fetal cardiovascular response to acute hypoxemia is characterized by bradycardia, hypertension, and redistribution of cardiac output. The role of aortic and carotid chemoreceptors in mediating these responses was examined in eight sinoaortic-denervated and nine shamoperated fetal lambs. Blood gases, pH, heart rate, arterial pressure, and blood flow distribution were determined before and during hypoxemia. In intact fetuses, heart rate fell from 184 +/- 12 to 165 +/- 23 beats/min (p less than 0.01) but increased from 184 +/- 22 to 200 +/- 16 beats/min (p less than 0.05) in the sinoaortic-denervated fetuses. Intact fetuses showed an early hypertensive response to hypoxemia, whereas the sinoaortic-denervated fetuses developed a delayed, progressive rise in blood pressure. In both groups, fetal cardiac output and umbilical blood flow were maintained; cerebral, myocardial, and adrenal blood flow increased, and pulmonary blood flow decreased. Peripheral blood flow decreased 39% (p less than 0.001) in intact fetuses but was maintained in sinoaortic-denervated fetuses. Vascular responses to hypoxia in the brain, heart, adrenal, and lungs are regulated primarily by direct local effects. During hypoxemia, peripheral chemoreceptors mediate bradycardia and peripheral vasoconstriction but do not appear to be crucial for immediate fetal survival.

Animals↗

Muscle denervation in peripheral arterial disease.

Muscle function is often severely impaired in peripheral arterial disease (PAD), but the effects of repeated ischemic events upon nerve and muscle are incompletely characterized. We performed comprehensive electrophysiologic studies and skeletal muscle histologic analysis in six patients with unilateral PAD and five control subjects matched for age and activity level. In the PAD patients, all ischemic legs showed both electrophysiologic and histologic evidence of chronic partial denervation-reinnervation restricted to distal muscles. Two of the PAD patients had evidence of milder distal denervation in the nonischemic legs. Two of the controls had denervation in at least one leg, but in each case electrophysiologic findings were pathognomonic of L-5 and S-1 radiculopathies. All other control legs and nonischemic legs were normal. These results suggest that recurrent ischemia associated with PAD may cause muscle denervation, which may be one of the mechanisms responsible for decreased exercise performance in these patients.

Action Potentials↗

MR features of the denervated tongue in radiation induced neuropathy.

The MR features of the denervated tongue have been described following nerve injury from radical neck dissection and tumour invasion. The purpose of the study was to determine whether similar features are present in the tongue following radiation induced neuropathy (RIN). The clinical records and MR images of 12 patients with RIN of the hypoglossal nerve were reviewed retrospectively. T1 weighted SE images were performed in 12, T2 weighted TSE images in 11, fat suppressed images in 10 and contrast enhanced T1 weighted images in nine patients. The denervated tongue revealed "oedemalike" changes in five, fatty infiltration in six, atrophy in 11 and pseudohypertrophy in one patient. Abnormal enhancement was not identified, and in five patients the signal intensity was normal on all sequences. The oedemalike changes, fatty infiltration and normal signal intensity were seen 2-48, 2-48, and 6-63 months, respectively, after the onset of RIN. In conclusion, there was no discernible relationship between the duration of RIN and the MR appearance of the denervated tongue. Oedemalike changes, previously described in the acute/subacute phase of denervation, were also seen in long-standing disease and there was no associated abnormal enhancement in any case. Furthermore, the signal intensity may be normal, the MR diagnosis relying on asymmetry of the size of the tongue. It is postulated that radiation causes incomplete and ongoing damage of the nerve, the course of which is unpredictable.

Adult↗