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PubMed2002

Transcriptional regulation of the type I myosin heavy chain gene in denervated rat soleus.

Denervation (DEN) of rat soleus is associated with a decreased expression of slow type I myosin heavy chain (MHC) and an increased expression of the faster MHC isoforms. The molecular mechanisms behind these shifts remain unclear. We first investigated endogenous transcriptional activity of the type I MHC gene in normal and denervated soleus muscles via pre-mRNA analysis. Our results suggest that the type I MHC gene is regulated via transcriptional processes in the denervated soleus. Deletion and mutational analysis of the rat type I MHC promoter was then used to identify cis elements or regions of the promoter involved in this response. DEN significantly decreased in vivo activity of the -3,500, -2,500, -914, -408, -299, and -215 bp type I MHC promoters, relative to the alpha-skeletal actin promoter. In contrast, normalized -171 promoter activity was unchanged. Mutation of the betae3 element (-214/-190) in the -215 promoter and deletion of this element (-171 promoter) blunted type I downregulation with DEN. In contrast, betae3 mutation in the -408 promoters was not effective in attenuating the DEN response, suggesting the existence of additional DEN-responsive sites between -408 and -215. Western blotting and gel mobility supershift assays demonstrated decreased expression and DNA binding of transcription enhancer factor 1 (TEF-1) with DEN, suggesting that this decrease may contribute to type I MHC downregulation in denervated muscle.

Animals↗

PubMed1977

Potassium and chloride conductances in normal and denervated rat muscles.

The membrane conductance of rat muscles (mainly gastrocnemius (G) and soleus (S)) was measured by using the two-microelectrode technique and the current point clamp method. Thin muscle bundles were washed in Tris chloride and Tris propionate solutions containing 6 mM K. The current strength was always 5 x 10-9 A and the steady-state membrane voltage was about 5 mV. The average chloride conductance (gcl, in mumho/cm2) of normal muscles was 845 (G) and 1,025 (S). The potassium conductance (gk) was 99 (G) and 161 (s). In separate measurements, the contribution of the chloride conductance (gcl) to the total membrane conductance (gm) was 89% for normal G and S. Two weeks after denervation the average gcl decreased to 440 in G and 191 in S; gk increased to 205 in G and to 364 in S in the presence of 0.1 mM Ca in solution; the increase in gk was less when measurements were made in the presence of 3mM Ca and 1 mM Mg. The contribution of gcl to gm was 60% in G and 30% in S in 14-day denervated muscles. The coefficient of variation for gcl/gk in 30 normal and 46 denervated muscles was 0.91 and 0.46, respectively. The curve representing the voltage-current relationship of muscles washed in Cl-free solutions containing 60 mM K was S-shaped in normal and in denervated muscles, but the changes in slope were less marked in the latter.

Animals↗

PubMed1998

Expression of adenylyl cyclase mRNAs in the denervated and in the developing mouse skeletal muscle.

Changes in the activity and in the expression of adenylyl cyclase (AC) were examined in mouse skeletal muscle after denervation and during development. Four isoforms of AC (AC2, AC6, AC7, and AC9) were detected by Northern blot analysis in gastrocnemius muscle, AC9 being the most abundant. After denervation, the levels of AC2 and AC9 mRNA decreased, whereas those of AC6 and AC7 increased. AC activity in response to several neurotransmitters was increased after denervation. During development, AC activity was high in fetus and neonate and declined in the adult; the sensitivity of AC activity to various neurotransmitters was the highest on the third postnatal day. The levels of AC6 and AC7 mRNAs were high on the third postnatal day and then decreased in adult, paralleling the decline in AC activity. All the characteristics of AC expression and activity in fetus and neonate resembled those observed in denervated adult muscle. These results indicate that changes in AC activity and AC mRNAs play an important role in the various physiopathological states of skeletal muscle, especially during muscle atrophy.

Adenylyl Cyclases↗

PubMed1984

Insulin resistance of denervated rat muscle: a model for impaired receptor-function coupling.

The effect of short-term denervation on the response to insulin was studied in isolated rat soleus and extensor digitorum longus (EDL) muscles 6 and 24 h after severing one sciatic nerve. Impaired insulin sensitivity and response occurred within 6 h postdenervation in solei. After 24 h, EDL of fed and fasted rats and solei of fed rats showed no stimulation of glycogen synthesis even with supraphysiological doses, whereas solei of fasted rats showed markedly decreased sensitivity and response to insulin. Insulin resistance of glycogen synthesis represented impaired stimulation of glucose transport and impaired glucose-independent activation of glycogen synthase by insulin. Changes in initial glycogen content of muscles did not correlate with insulin resistance. Insulin binding after denervation showed only minimum impairment and did not account for the marked insulin resistance. The response of denervated solei to epinephrine was unimpaired. Insulin resistance, which develops early after denervation in red and white muscles, represents primarily a defect in receptor-function coupling, suggesting that in muscle, nervous stimuli and/or contractile activity modulate signal transmission by the occupied insulin receptor.

Animals↗

PubMed1985

Glucose turnover during insulin-induced hypoglycemia in liver-denervated rats.

The role of hepatic autonomic nerves in glucose production during hypoglycemia was studied. Selective, surgical denervation of the liver was performed in rats, which reduced hepatic norepinephrine concentrations by 96%. Hypoglycemia was induced by 250 mU of insulin intra-arterially in anesthetized as well as in chronically catheterized, awake rats. Half of the anesthetized denervated or sham-operated rats had previously been adrenodemedullated. Glucose turnover was measured by primed, constant intravenous infusion of [3-3H]glucose. Before as well as during hypoglycemia the arterial glucose concentration and rates of production and utilization of glucose were similar in denervated rats and control rats. Also hepatic glycogen depletion was similar in the groups. The lack of effect of denervation could not be ascribed to compensating changes in hormone or substrate levels. In adrenodemedullated rats lack of glucose recovery from hypoglycemia was accompanied by delayed normalization of glucose clearance. In fed rats, activity in hepatic autonomic nerves is not a primary mechanism increasing glucose production during acute hypoglycemia. Epinephrine enhances glucose recovery by decreasing glucose clearance rather than by increasing glucose production, at least when glucagon is present.

Adrenal Cortex Hormones↗

PubMed1987

Clenbuterol, a beta 2-agonist, retards atrophy in denervated muscles.

Denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, contained 95-110% more protein after 2-3 wk of treatment with the adrenergic beta 2-receptor agonist, clenbuterol, than denervated controls. In addition, the twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area. In contrast, when the innervated contralateral muscles were examined, the extensor digitorum longus and anterior tibialis showed relatively small increases in protein of 32 and 19%, respectively, whereas the soleus and gastrocnemius were unaffected. The magnitude of the effects of clenbuterol in sparing the mass and functional capacity of denervated muscle suggests that this agent may be important in studies of neuromuscular diseases and disuse atrophy.

Animals↗

PubMed1989

Selective in vitro reversal of the insulin resistance of glucose transport in denervated rat skeletal muscle.

Denervation (24 h) of skeletal muscle causes severe postreceptor insulin resistance of glucose transport and glycogen synthesis that is demonstrable in isolated muscles after short (30 min) preincubations. After longer preincubations (2-4 h), the insulin response of glucose transport increased to normal, whereas glycogen synthesis remained insulin resistant. Basal and insulin-stimulated amino acid transport were significantly lower in denervated muscles than in controls after short or long incubations, although the percentage stimulation of transport by insulin was not significantly different. The development of glucose transport insulin resistance after denervation was not attributable to increased sensitivity to glucocorticoids or adenosine. The selective in vitro reversal of glucose transport insulin resistance was not dependent on medium composition, did not require protein or prostaglandin synthesis, and could not be attributed to release of a positive regulator into the medium. The data suggest 1) the insulin receptor in muscle stimulates glucose transport by a signaling pathway that is not shared by other insulin-sensitive effector systems, and 2) denervation may affect insulin receptor signal transduction at more than one site.

Adenosine↗

PubMed1991

Effect of baroreceptor denervation on stimulation of drinking by angiotensin II in conscious dogs.

Angiotensin II causes marked stimulation of drinking when it is injected centrally but is a relatively weak dipsogen when administered intravenously. However, it has been proposed that the dipsogenic action of systemically administered angiotensin II may be counteracted by the pressor action of the peptide. To test this hypothesis, the dipsogenic action of angiotensin II was investigated in dogs, in which low and high baroreceptor influences had been eliminated by denervation of the carotid sinus, aortic arch, and heart. In five sham-operated dogs, infusion of angiotensin II at 10 and 20 ng.kg-1.min-1 increased plasma angiotensin II concentration to 109.2 +/- 6.9 and 219.2 +/- 38.5 pg/ml and mean arterial pressure by 20 and 29 mmHg, respectively, but did not induce drinking. In four baroreceptor-denervated dogs, the angiotensin II infusions produced similar increases in plasma angiotensin II concentration and mean arterial pressure but, in contrast to the results in the sham-operated dogs, produced a dose-related stimulation of drinking. Water intake with the low and high doses of angiotensin II was 111 +/- 44 and 255 +/- 36 ml, respectively. The drinking responses to an increase in plasma osmolality produced by infusion of hypertonic sodium chloride were not different in the sham-operated and baroreceptor-denervated dogs. These results demonstrate that baroreceptor denervation increases the dipsogenic potency of intravenous angiotensin II and provides further support for the hypothesis that the dipsogenic action of intravenous angiotensin II is counteracted by the rise in blood pressure.

Angiotensin II↗

PubMed1987

Effect of intestinal denervation on intestinal vascular response to severe arterial hypoxia in newborn swine.

We examined the effects of alpha-adrenergic blockade (phentolamine) and intestinal denervation on the circulatory response of the newborn swine intestine to severe arterial hypoxia. Intestinal vascular resistance significantly increased during severe arterial hypoxia in the control group, whereas no change in intestinal vascular resistance was observed in the phentolamine or denervation groups at this time. Intestinal perfusion pressure increased in the control group but decreased in the phentolamine and denervation groups during severe arterial hypoxia. Despite the difference in intestinal vascular resistance, intestinal blood flow decreased in a similar manner in all groups during severe arterial hypoxia. Intestinal arteriovenous O2 content difference [(a-v)O2] and O2 uptake were greater during severe arterial hypoxia in the phentolamine and denervation groups than in the control group. We speculate that the sympathetic stimulation mediates the increase in intestinal vascular resistance in newborn swine during severe arterial hypoxia; and sympathetic stimulation limits the increase in intestinal (a-v)O2, which occurs during severe arterial hypoxia in the newborn swine intestine.

Animals↗

PubMed1990

Evaluation of selective liver denervation methods.

This study compares four methods of hepatic denervation and defines the rate and physiological significance of reinnervation. Five groups of rats were prepared: 10 underwent orthotopic liver transplantation. In nine rats a 90% aqueous phenol solution was applied circumferentially to the portal vein. Thirteen rats underwent microsurgical denervation; 28 received different doses of 6-hydroxydopamine (6-HODA) administered as a single intraportal injection [50 (n = 10), 75 (n = 6), and 100 mg/kg (n = 6)]. Twelve rats were studied as controls. Rats were killed 1, 4, and 8 wk after surgery to determine liver tissue content of norepinephrine (NE). Changes in mean arterial pressure (MAP) in response to hepatic nerve stimulation, which was supramaximum in intensity and frequency, were measured before rats were killed. NE content in controls ranged from 121 to 204 ng/g and MAP increased by 30-38 mmHg after electrical stimulation. At 1, 4, and 8 wk after treatment the liver NE content was less than 1, 2.3, and 20.2 ng/g in the transplant group; less than 1, 2.7, 4.1 ng/g in the phenol group; and 17.2, less than 1, and 3 ng/g in the surgically denervated group. In the 6-HODA group, values were 18.9, 47, and 61.5 ng/g (50 mg/kg); 5.7, 20.2, and 15 ng/g (75 mg/kg); and 7.7, 2.5, and 17.5 ng/g (100 mg/kg). When the level of NE was undetectable, MAP increase after stimulation was 0-18% that of controls. When NE content was 15-23% of normal, MAP increased 49-62% regardless of the denervation technique.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Liver denervation does not alter the circadian rhythm of bile acid synthesis in rats.

In both rats and humans there is a distinct circadian rhythm of bile acid synthesis that is independent of feedback regulation. To determine whether the circadian rhythm is directly mediated via hepatic nerves, bile acid synthesis was studied in selectively liver-denervated male Sprague-Dawley rats in a bile fistula model. Complete denervation was confirmed by histofluorescent staining for neural elements in frozen sections of livers. There was no significant difference in mean bile acid synthesis, amplitude of the circadian rhythm, or time of peak synthesis between the denervated rats and nondenervated controls. In one denervated rat studied four times at weekly intervals, there was no shift in acrophase, indicating that the rhythm had not become free running. We conclude that signals arriving via hepatic nerves neither directly cause nor entrain the circadian rhythm of bile acid synthesis in rats.

Animals↗

PubMed1997

A unique myosin isoform transition in cat striated external anal sphincter muscle induced by denervation.

Denervation of limb and trunk muscles leads to characteristic changes in their biochemical properties. However, the effects of denervation of the striated external anal sphincter (EAS) muscle have not been studied, even though denervation is a common etiology for fecal incontinence. The present study reports effects ofdenervation of the cat EAS and compares them with changes in a denervated limb muscle [cat extensor digitorum longus (EDL)]. Nerves supplying the EAS and the EDL were sectioned in anesthetized cats, which were allowed to recover and live for 10, 30, or 60 days. Their muscles were then excised, and myofibrillar proteins were isolated. Myosin heavy chain (MHC) isoform composition was measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The EDL and EAS showed progressive increases in MHC type IIA and progressive decreases in MHC type IIB at 10, 30, and 60 days. MHC type I progressively increased in the EDL but showed no change in the EAS. We hypothesize that this distinctive transition is related to the unique embryological origin and function of the EAS.

Anal Canal↗

PubMed1983

Vasopressin and renin responses to hemorrhage in conscious, cardiac-denervated dogs.

We measured plasma arginine vasopressin (AVP) and plasma renin activity (PRA) during continuous hemorrhage in cardiac-denervated and sham-operated conscious dogs. Hemorrhage produced comparable decreases in aortic pressure, cardiac output, stroke volume, pulmonary arterial pressure, and left and right atrial pressures in each group of dogs. After 10 ml blood/kg body wt had been removed, AVP was increased in sham-operated dogs (P less than 0.05) but not in cardiac-denervated dogs. After 20 and 30 ml blood/kg body wt had been removed, AVP was increased in all dogs, but the response was markedly attenuated in cardiac-denervated dogs. Hemorrhage at 10 and 20 ml/kg caused comparable increases in PRA in each group of dogs. However, at 30 ml/kg hemorrhage the increase in PRA was significantly higher in cardiac-denervated dogs than in sham-operated dogs. Our results suggest that cardiac receptors play a dominant role in mediating the release of AVP during hemorrhage in conscious dogs. In contrast, we found no evidence for a dominant role of cardiac receptors in mediating renin secretion during hemorrhage.

Animals↗

PubMed1984

Influence of cardiac denervation on subsidiary atrial pacemaker stabilization.

Overdrive suppression was determined by measuring cardiac cycle lengths after rapid atrial pacing in nine alert conscious dogs sustaining total intrapericardial denervation. Rapid atrial pacing was performed at 125-400% of spontaneous heart rate for 30 s and at 200% spontaneous rate for 30, 60, 120, and 180 s, with and without cholinergic (atropine 0.2 mg/kg iv) or adrenergic blockade (propranolol 0.5 mg/kg iv). Corrected recovery time (CRT) was defined as the first recovery cycle length minus average control cycle length. To compare responses of the intact sinoatrial node (SAN) and subsidiary atrial pacemakers, CRT was measured in the conscious animal before and after SAN excision. Immediately after SAN excision, a junctional rhythm was frequently observed, but within a short time (min-h), subsidiary atrial pacemaker dominance was established with well-formed P waves and P-R interval averaging 85.3 +/- 3.4 ms. CRT before SAN excision ranged from 100 to 300 ms. Following pacing at 125-400% of spontaneous heart rate soon after SAN excision, CRT was markedly prolonged, ranging up to 6,000 ms. Atropine and propranolol did not influence CRT in the denervated preparation. CRT of subsidiary atrial pacemakers in the normally innervated dog heart returned to control pre-SAN excision values in 1-2 wk. In the denervated heart complete autonomic denervation exaggerated time required for return to control CRT values to 5-8 wk.

Animals↗

PubMed1988

Blood flow in normal and denervated muscle during exercise in conscious rats.

The purpose of this study was to test the hypothesis that extrinsic mechanical factors, i.e., the dynamic shortening and lengthening imposed on a muscle during limb movements and the rhythmic compressions as surrounding muscles contract and relax, contribute to the initial muscle hyperemia during locomotion in conscious male Sprague-Dawley rats. Soleus and lateral head of gastrocnemius muscles were surgically denervated in one hindlimb several hours before exercise to remove 1) local metabolic vasodilator effects, 2) vasoconstrictor or vasodilatory influences mediated through sympathetic postganglionic fibers, and 3) intrinsic mechanical pumping. Blood flow was measured with radioactive microspheres during preexercise and at 30 s and 5 min of exercise in rats walking at 15 m/min or a motor-driven treadmill. Glycogen concentrations were also measured as an indicator of muscular activity to verify the denervation. Blood flows to control muscles in the normal limb were similar to previously reported values during preexercise and exercise. Denervation, however, decreased preexercise blood flow (69-88%) to muscle composed predominantly of oxidative fibers and increased flow (53%) to muscle composed predominantly of glycolytic fibers. During exercise, blood flow to denervated muscles either remained unchanged or decreased. These data suggest that extrinsic mechanical factors do not significantly contribute to the initial hyperemic response at the onset of low-intensity exercise in normal muscle.

Animals↗

PubMed1992

Vasoactive intestinal peptide in canine hearts: effect of total cardiac denervation.

The effect of total cardiac denervation on the distribution of cardiac immunoreactive vasoactive intestinal peptide (IR-VIP) was determined in four groups of dogs. Denervated dogs killed at either 7 days (group 1) or 30 days (group 3) were compared with sham-operated dogs killed at either 7 days (group 2) or 30 days (group 4). The highest concentrations of IR-VIP were found in the left atrium and proximal left anterior descending and circumflex coronary arteries and were not affected by denervation. Concentrations of IR-VIP in the left ventricle were barely detectable. Only right ventricular IR-VIP concentrations were significantly lower in denervated compared with sham-operated dogs in both groups. Thus these data provide evidence of intrinsic VIP innervation of the atria and epicardial coronary arteries and localized extrinsic VIP innervation of the right ventricle of the canine heart.

Animals↗

PubMed1995

Effects of renal denervation on cardiovascular response to furosemide in conscious lambs.

The cardiovascular response to furosemide in the newborn and the role of renal sympathetic nerves in influencing this response have not been investigated. We hypothesized that in conscious lambs, furosemide would decrease blood pressure, the response being accentuated in the absence of renal sympathetic nerves. Pulsatile pressures and heart rates were measured before and after furosemide (2 mg/kg) administration to chronically instrumented lambs with either bilateral renal denervation (denervated, n = 8) or renal nerves intact (intact, n = 6). In intact lambs, mean arterial pressure remained constant after furosemide; in denervated lambs there was an increase in arterial pressure 20 min after furosemide (P < 0.001), and control levels were reached by 100 min. Basal heart rate was higher in denervated than in intact lambs (P = 0.009). In both groups of lambs, heart rate increased 40 min after furosemide and remained elevated. These data provide new information that, in conscious newborn animals, renal sympathetic nerves influence the blood pressure response to furosemide, as well as basal control of heart rate.

Animals↗

PubMed2002

Sensitive periods for the effect of dietary sodium restriction on intact and denervated taste receptor cells.

Unilateral chorda tympani nerve (CT) section combined with dietary sodium restriction leads to striking alterations in sodium taste function. The regenerated rat CT exhibits deficits in sodium sensitivity, and surprisingly, there are also functional alterations in the intact, contralateral nerve. The studies presented here describe the functional "sensitive periods" for these aberrations and the number of taste buds present during corresponding stages. The regenerated CT is sensitive to dietary sodium restriction during the first 2 wk after denervation, whereas the intact CT is sensitive to dietary manipulation during the first week postsection. Therefore, distinct mechanisms are responsible for the effects of sodium restriction combined with denervation, because separate sensitive periods exist for the regenerated and intact CT nerves. Identification of mature taste buds with an antibody directed at anti-keratin 19 revealed that there is a loss of ~85% of taste buds on the denervated side of the tongue under control and low-sodium diets within the first week postsection. Thus, sodium restriction does not differentially affect the loss of taste buds following denervation.

Animals↗