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PubMed1987

Hepatic denervation alters first-phase urinary sodium excretion in dogs with cirrhosis.

Cirrhotic dogs without intrahepatic hypertension (IHH) never retain sodium or expand plasma volume. To test the hypothesis that IHH may cause urinary sodium retention early in cirrhosis, we prepared cirrhotic dogs (chronic biliary obstruction) who underwent simultaneous hepatic denervation with end-side portacaval anastomoses. Such animals, along with appropriate controls and unanesthetized were studied by balance techniques. In the experimental group, plasma volume never increased, and sodium retention did not occur until 2 days prior to the appearance of detectable ascites. In a sham-denervated group, plasma volume increased by 10% and sodium retention occurred on the average 8.4 days prior to ascites. When the portal veins were left intact, the sham-denervated group showed the usual magnitude of plasma volume expansion observed in cirrhotic dogs (18.3%) with a 7-day delay between sodium retention and ascites appearance. Those dogs with hepatic denervation demonstrated a 9.2-day delay with 12.6% expansion of plasma volume. When ascites was mobilized with a peritoneovenous valve, and dogs were subjected to a high salt diet (130 meq/day), denervated dogs excreted the load normally, whereas sham-denervated dogs retained sodium and developed anasarca. We conclude that in cirrhotic dogs with IHH, liver denervation prevents early non-volume-related sodium retention.

Animals↗

PubMed1990

Intrapericardial denervation: radial artery blood flow and heart rate responses to LBNP.

Eight rhesus monkeys were used to study responses of radial artery blood flow velocity (RABFV) and heart rate (HR) to low (0 to -20 mmHg) and high (0 to -60 mmHg) ramp exposures during supine lower body negative pressure (LBNP). These levels were chosen to separate peripheral vascular responses associated with stimulation of low- and high-pressure baroreceptors. Four monkeys had efferent and afferent cardiac denervation by use of the Randall procedure with pharmacological (phenylephrine and atropine) verification. Animals were studied 3 wk after surgery to avoid reinnervation. Findings were compared with those of four identically treated intact animals. Denervated animals showed no change in RABFV or HR during low-level LBNP; however, HR increased significantly (P less than 0.05) when LBNP reached -50 mmHg and blood flow velocity also fell (P less than 0.05) starting at -30 mmHg pressure. In contrast, intact animals showed steady decreases in RABFV during both high- and low-pressure protocols, with HR showing a 6-beat/min increase (P less than 0.05) starting at -20 mmHg pressure. As with denervated animals, intact animals showed a more pronounced increase in HR after reaching a level of -60 mmHg suction. Cardiac output (electromagnetic flowmeter, ascending aorta) fell significantly in both groups starting at -30 mmHg pressure. Left ventricular pressure (Konigsberg pressure cell) in three intact animals showed a progressive fall in systolic pressure starting at -10 mmHg suction, which became significant at -55 mmHg pressure. These results demonstrate that cardiac denervation by use of the Randall technique significantly affects RABFV and HR responses to LBNP in rhesus monkeys. The lack of RABFV change during LBNP in denervated animals suggests that these changes coupled with HR response can be used as an effective method to verify the completeness of denervation of low-pressure baroreceptors in animals that have undergone intrapericardial denervation.

Animals↗

PubMed2005

Denervation in murine fast-twitch muscle: short-term physiological changes and temporal expression profiling.

Denervation deeply affects muscle structure and function, the alterations being different in slow and fast muscles. Because the effects of denervation on fast muscles are still controversial, and high-throughput studies on gene expression in denervated muscles are lacking, we studied gene expression during atrophy progression following denervation in mouse tibialis anterior (TA). The sciatic nerve was cut close to trochanter in adult CD1 mice. One, three, seven, and fourteen days after denervation, animals were killed and TA muscles were dissected out and utilized for physiological experiments and gene expression studies. Target cDNAs from TA muscles were hybridized on a dedicated cDNA microarray of muscle genes. Seventy-one genes were found differentially expressed. Microarray results were validated, and the expression of relevant genes not probed on our array was monitored by real-time quantitative PCR (RQ-PCR). Nuclear- and mitochondrial-encoded genes implicated in energy metabolism were consistently downregulated. Among genes implicated in muscle contraction (myofibrillar and sarcoplasmic reticulum), genes typical of fast fibers were downregulated, whereas those typical of slow fibers were upregulated. Electrophoresis and Western blot showed less pronounced changes in myofibrillar protein expression, partially confirming changes in gene expression. Isometric tension of skinned fibers was little affected by denervation, whereas calcium sensitivity decreased. Functional studies in mouse extensor digitorum longus muscle showed prolongation in twitch time parameters and shift to the left in force-frequency curves after denervation. We conclude that, if studied at the mRNA level, fast muscles appear not less responsive than slow muscles to the interruption of neural stimulation.

Animals↗

PubMed1977

Increased histaminase activity in the atrophic muscle of denervated frog.

Sciatic denervation for 1 month in the frog Rana hexadactyla resulted in progressive atrophy of the gastrocnemius muscle without any change in the total DNA content of the whole muscle. Histamine content of the muscle decreased; glutamic and acid content increased and histidine level remained unaltered on denervation. Histaminase activity localized in the muscle decreased; glutamic acid content increased and histidine level remained unaltered on denervation. Histaminase activity localized in the muscle mitochondria increased on denervation. The histidine-degrading enzymes, histidine ammonia lyase, urocanate hydratase and imidazol-5yl lactate dehydrogenase, are localized in the sarcoplasm of the muscle and their activities are not altered on denervation. The histidine decarboxylase activity localized in the mitochondria is not altered on denervation. The reduction in the histamine content of the atrophied muscle may be due to increased mitochondrial histaminase activity but not due to increased decarboxylation of histidine. The loss of 'trophic influence' due to denervation may be manifested in the impairment of mitochondrial histaminase activity.

Acetylcholine↗

PubMed1992

Effect of selective denervation of baroreceptors on pulmonary ventilation and arterial pressure lability in rat.

Earlier studies report that sinoaortic baroreceptor denervation (SAD) in rats causes moderate elevation of mean arterial pressure along with a marked increase of arterial pressure lability (APL). In this context, we studied the effects of selective aortic denervation (AD) or selective carotid denervation (CD) on the regulation of blood pressure. In addition, we evaluated the effects of selective or total baroreceptor denervation on pulmonary ventilation and ventilation-related changes of arterial pressure. Mean arterial pressure was evaluated by computer-assisted techniques, and ventilation was measured by whole body plethysmography on conscious freely moving rats. With this approach, equal increases of mean arterial pressure were obtained for rats that had undergone AD, CD, and SAD. The APL was higher in SAD rats than in selectively denervated rats. CD and AD rats had an elevated APL relative to sham-operated animals, and its increase was approximately equal for the two selectively denervated groups. Total as well as selective denervation had relatively small effects on ventilation and on the general pattern of breathing. In all groups, this pattern consisted of regular ventilation, periodically interrupted by single deeper breaths. In SAD, AD, and CD animals, these larger tidal volumes were associated with marked transient reductions of mean arterial pressure, whereas small decreases of pressure occurred in sham-operated rats. The results indicate that both groups of baroreceptors must be present to keep mean arterial pressure at its normal level. Moreover, both receptor groups are equally important in reducing APL. Ventilation contributes to generation of APL after total or selective baroreceptor removal. Such ventilation-induced pressure changes are kept at a minimum in baroreceptor-intact rats.

Animals↗

PubMed1995

Aortic distensibility and structural changes in sinoaortic-denervated rats.

The purpose of the present study was to determine the effects of chronic sinoaortic denervation on the mechanical properties and composition of the abdominal aorta in Wistar rats. We used a high-resolution echotracking system to determine in situ under physiological conditions of blood flow and arterial wall innervation the aortic diameter-, compliance-, and distensibility-pressure curves in 16-week-old anesthetized rats that had been denervated at 10 weeks of age for 6 weeks (n = 8). Compared with sham-operated rats (n = 8) we observed a marked reduction of baroreflex response and increase in overall mean blood pressure variability as measured by standard deviation and spectral analysis in sinoaortic-denervated rats. Mean blood pressure was not affected by sinoaortic denervation in both conscious and anesthetized rats. Sinoaortic denervation significantly shifted the distensibility-pressure curve toward lower levels of distensibility, indicating a decreased aortic distensibility for a given level of arterial pressure. Sinoaortic denervation produced a significant increase of aortic wall cross-sectional area and collagen content, one of the less-distensible components of the arterial wall. These results suggest that intact arterial baroreceptors are necessary for maintaining normal functional and structural properties of large arteries in rats. The reduction in arterial distensibility in chronic sinoaortic-denervated rats may have resulted from different factors, including the initial hypertensive phase, aortic wall hypertrophy, and increase in collagen content. The changes in aortic wall structure and related reduction in aortic distensibility, in addition to other mechanisms, might have been direct consequences of an increased blood pressure variability.

Animals↗

PubMedDate not supplied

Effect of renal denervation on arterial pressure in rats with aortic nerve transection.

The role of renal nerves in influencing the control of arterial pressure was studied in Wistar rats with aortic depressor nerve (ADN) transection. Renal denervation prevented or reversed the normal increase in arterial pressure seen after ADN transection. This effect was not due to an effect on the renin-angiotensin system, as the elevated arterial pressure after ADN section in rats with renal nerves intact was shown to be due to increased alpha-adrenergic activity. Food and water intake and urine output decreased significantly in both renal-denervated and sham-denervated rats after ADN section, suggesting that a pressure diuresis mechanism was not responsible for preventing the rise in pressure in renal-denervated rats. In another study, the concentration of norepinephrine in skeletal muscle and hypothalamus at 0 and 8 hours after inhibition of tyrosine hydroxylase with alpha-methyltyrosine was used as an index of norepinephrine turnover. Norepinephrine turnover in skeletal muscle was increased significantly over control values by ADN transection in sham renal-denervated rats, but was not significantly different from controls in renal-denervated rats with ADN section. In the hypothalamus, there was a significant difference between the turnover of norepinephrine in the two groups of ADN-sectioned rats. The results taken together suggest that renal denervation prevents the arterial pressure response to ADN transection by altering the central mechanisms governing sympathetic outflow. It is suggested that this effect may be due to elimination of information carried by afferent renal fibers.

Animals↗

PubMedDate not supplied

Effects of baroreceptor denervation on volume loading hypertension in anephric dogs.

The role of the baroreceptor mechanism in determining the relationship between fluid volume and arterial pressure is not clear. Therefore, the effects of the baroreflex on the arterial pressure and fluid volume of conscious, anephric dogs were studied after a sustained 10% increase in blood volume. The animals were equipped with long-term indwelling arterial and venous catheters, and arterial pressure was monitored 24 hours a day. The increase in blood volume was achieved by intravenous infusion of 50 ml/kg of lactated Ringer's solution in 30 minutes. After volume loading arterial pressure increased rapidly to hypertensive levels (130.8 +/- 7.5% of control) in a baroreceptor denervated group. The initial increase in arterial pressure in a group of normally innervated dogs was smaller (118.8 +/- 1.8% of control), but by 24 hours postinfusion the arterial pressure of both groups had reached the same level. The innervated group had probably experienced baroreceptor resetting by this time. Blood volume both before and after infusion was not different in the denervated and innervated groups; however, sodium space was markedly higher before the infusion in the denervated dogs (431.8 +/- 13.8 ml/kg vs 344.8 +/- 19.0 ml/kg in the innervated dogs), and the volume load caused parallel increases in this space in the denervated and innervated groups. The present study shows that the blood volume of anephric dogs was unchanged after baroreceptor denervation while the extracellular fluid volume of denervated dogs was elevated. Furthermore, a small sustained increase in blood volume in either conscious, innervated dogs or conscious, baroreceptor denervated dogs, in contradistinction to the effects in anesthetized dogs, resulted in significant increases in arterial pressure (p less than 0.05).

Animals↗

PubMed1986

Comparison of 1-hour and 24-hour blood pressure recordings in central or peripheral baroreceptor-denervated rats.

We compared the mean arterial pressure and heart rate activity of conscious, unrestrained rats during 1-hour and 24-hour continuous recording sessions, 3 to 4 weeks after either sinoartic denervation, placement of electrolytic lesions in the nucleus tractus solitarii, or sham operations. Sinoaortic denervation and nucleus tractus solitarii lesions both eliminated the reflex bradycardia to a phenylephrine-induced pressor response. No difference was found in the average level and lability of the mean arterial pressure between 1-hour and 24-hour recordings for any group. No elevation in the average mean arterial pressure of rats with nucleus tractus solitarii lesions was observed, although a mild hypertension was noted in half the sinoarotic-denervated rats, while the other half were normotensive. Group differences were not found for heart rate or heart rate variability; however, 24-hour recordings yielded significantly higher values than 1-hour recordings for all groups. Both medullary lesions and sinoaortic denervation significantly increased the lability of the mean arterial pressure, but the magnitude of the increase was significantly greater in the rats with lesions. The lability of the mean arterial pressure in sinoaortic-denervated rats depended largely on movement-related depressor responses that produced a negative skew in the frequency distribution of their mean arterial pressure. Rats with nucleus tractus solitarii lesions exhibited both pressor and depressor responses that resulted in pressure distributions that had a slight positive skew similar to that displayed by control rats. It is concluded that short-term continuous recordings of mean arterial pressure and heart rate accurately estimate the altered cardiovascular activity of baroreceptor-denervated rats. The differences in the cardiovascular responses of central and peripheral baroreceptor-denervated rats are believed to be due to the more extensive destruction by nucleus tractus solitarii lesions of central neurons and pathways involved in cardiovascular regulation.

Animals↗

PubMed1981

Hypertension following arterial baroreceptor denervation in the unanesthetized dog.

Studies were conducted on unanesthetized dogs (1) in the control state, (2) after carotid sinus denervation plus section of the cervical aortic nerves (SCAD), and (3) after carotid sinus denervation plus section of intrathoracic vegal branches which innervate arterial and cardiopulmonary baroreceptors, the heart, lungs, and other structures (STD). Mean values and standard deviations of blood pressure and heart rate were measured during many 75-minute recording sessions. The control mean arterial pressure was 94.8 +/- 8.9 mm Hg. The mean pressure after SCAD was 105.5 +/- 9.5 mm Hg, 10.0 mm Hg higher (P less than 0.05) than in the control state, whereas after STD, the mean pressure was 119.5 +/- 16.8 mm Hg, 25.3 mm Hg higher (P less than 0.001) than in the control state. The standard deviation of pressure was increased (P less than 0.01) by either denervation procedure. The mean pressure after STD was higher than after SCAD (P less than 0.05). Ten of 12 animals with SCAD showed residual baroreceptor reflexes (seven from intrathoracic receptors) whereas, after STD, six of 11 animals showed reflexes (one from intrathoracic receptors). SCAD only occasionally produces denervation as complete as that produced by STD. A larger increase in arterial pressure follows a more complete denervation of vagally innervated baroreceptors. We believe that our procedures do not denervate all arterial baroreceptors. Chronic denervation of arterial baroreceptors leads to a widely varying, elevated arterial pressure. The increase in pressure has persisted more than 1 1/2 years.

Animals↗

PubMed1991

Arterial wall and smooth muscle cell development in young Wistar rats and the effects of surgical denervation.

Development of the muscular saphenous artery and the effect of surgical denervation on normal development was investigated in young rats at 3 and 6 weeks of age. During this interval, the weight and blood pressures (systolic, diastolic, and mean) of the animals increased significantly. The tunica media of the artery and the lumen increased significantly with age, but the proportion of smooth muscle cell to paracellular matrix did not alter. Computer-assisted three-dimensional reconstructions were used to investigate the smooth muscle cells. They increased significantly in length, volume, and angle of orientation within the vessel wall with age but maintained an approximate surface area-to-volume ratio. The cells in any one vessel tended to be oriented in either a clockwise or counterclockwise direction. The size of the nucleus also increased significantly in length and volume with age, but an approximate surface area-to-volume ratio and a constant nucleocytoplasmic ratio were maintained. The nuclei tended to be eccentrically located, with less than half of all nuclei wholly within the middle third of the cell. Surgical denervation at 10 days of age resulted in abnormalities of growth in vessel dimensions, thinner tunica media at 3 weeks (denervated 11 days previously), and smaller lumen at 6 weeks (denervated 32 days previously). Elevated amounts of paracellular matrix occurred in both age groups, but denervation did not alter smooth muscle cell size. In the 3-week-old animals, denervation resulted in smooth muscle cells with hypertrophied nuclei. This may account for the increase in growth of the tunica media between 3 and 6 weeks of age in the denervated artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1982

Decrease in peripheral sympathetic nervous system activity following renal denervation or unclipping in the one-kidney one-clip Goldblatt hypertensive rat.

Increased sympathetic nervous system activity has been demonstrated in established one-kidney one-clip hypertension in the rat. We have found that renal denervation in this model results in an attenuation of hypertension, unassociated with alterations in sodium or water balance or renin activity. To determine whether the depressor effect of renal denervation is associated with changes in peripheral sympathetic nervous system activity, sham operation (n = 12), renal denervation (n = 13), or unclipping (n = 13) was carried out 2 wk after the onset of one-kidney one-clip hypertension. Normotensive unine-phrectomized age- and sex-matched rats were used as controls (n = 14). Renal denervation resulted in a significant decrease in systolic blood pressure (201+/-7 to 151+/-6 mm Hg), while unclipping lowered systolic blood pressure to normotensive levels (130+/-6 mm Hg). 8 d after operation plasma norepinephrine and mean arterial pressure before and after ganglionic blockade with 30 mg/kg hexamethonium bromide were measured in conscious, unrestrained, resting animals, as indices of peripheral sympathetic nervous system activity. Plasma norepinephrine was significantly higher in hypertensive sham-operated rats (422+/-42 pg/ml) compared with normotensive controls (282+/-25 pg/ml) (P < 0.01). Both renal denervation and unclipping restored plasma norepinephrine to normal levels (273+/-22 and 294+/-24 pg/ml, respectively). Ganglionic blockade in hypertensive sham-operated animals resulted in a significantly greater decrease in mean arterial pressure than occurred in renal denervated, unclipped, or control rats. The data suggest that the depressor effect of renal denervation or unclipping in the one-kidney one-clip hypertensive rat is associated with a decrease in peripheral sympathetic nervous system activity.

Animals↗

PubMed2006

Reduction of skeletal muscle atrophy by a proteasome inhibitor in a rat model of denervation.

The ubiquitin-proteasome system is the primary proteolytic pathway implicated in skeletal muscle atrophy under catabolic conditions. Although several studies showed that proteasome inhibitors reduced proteolysis under catabolic conditions, few studies have demonstrated the ability of these inhibitors to preserve skeletal muscle mass and architecture in vivo. To explore this, we studied the effect of the proteasome inhibitor Velcade (also known as PS-341 and bortezomib) in denervated skeletal muscle in rats. Rats were given vehicle or Velcade (3 mg/kg po) daily for 7 days beginning immediately after induction of muscle atrophy by crushing the sciatic nerve. At the end of the study, the rats were euthanized and the soleus and extensor digitorum longus (EDL) muscles were harvested. In vehicle-treated rats, denervation caused a 33.5 +/- 2.8% and 16.2 +/- 2.7% decrease in the soleus and EDL muscle wet weights (% atrophy), respectively, compared to muscles from the contralateral (innervated) limb. Velcade significantly reduced denervation-induced atrophy to 17.1 +/- 3.3% in the soleus (P < 0.01), a 51.6% reduction in atrophy associated with denervation, with little effect on the EDL (9.8 +/- 3.2% atrophy). Histology showed a preservation of muscle mass and preservation of normal cellular architecture after Velcade treatment. Ubiquitin mRNA levels in denervated soleus muscle at the end of the study were significantly elevated 120 +/- 25% above sham control levels and were reduced to control levels by Velcade. In contrast, testosterone proprionate (3 mg/kg sc) did not alleviate denervation-induced skeletal muscle atrophy but did prevent castration-induced levator ani atrophy, while Velcade was without effect. These results show that proteasome inhibition attenuates denervation-induced muscle atrophy in vivo in soleus muscles. However, this mechanism may not be operative in all types of atrophy.

Animals↗

PubMed1988

Effect of baroreceptor denervation on the inhibition of renin release by vasopressin.

Previous studies have suggested that the inhibition of renin secretion by acute administration of vasopressin in conscious dogs results from a reflex reduction in renal nerve activity. In the present investigation, this hypothesis was tested by studying the effect of total baroreceptor denervation or selective low pressure baroreceptor denervation on the suppression of PRA by vasopressin in conscious, chronically prepared dogs. In eight sham-operated dogs, a 45-min infusion of vasopressin (2.0 ng/kg.min, iv) decreased PRA from 10.5 +/- 1.9 to 5.9 +/- 1.0 ng/ml.3 h (P less than 0.01). Mean arterial pressure did not change (110 +/- 10 to 107 +/- 7 mm Hg), but heart rate decreased from 84 +/- 9 to 69 +/- 8 beats/min (P less than 0.05). In contrast, vasopressin infusion failed to significantly decrease PRA in seven sinoaortic/cardiac denervated dogs (9.5 +/- 1.7 to 7.4 +/- 2.0 ng/ml.3 h), although decreases did occur in three of the dogs. Mean arterial pressure increased from 104 +/- 5 to 125 +/- 6 mm Hg (P less than 0.01), but heart rate did not change (112 +/- 4 to 107 +/- 5 beats/min). When renal perfusion pressure was maintained at the preinfusion level in three sinoaortic/cardiac denervated dogs, vasopressin infusion failed to decrease PRA (2.3 +/- 0.6 to 2.4 +/- 0.6 ng/ml.3 h). In six cardiac denervated dogs, vasopressin infusion decreased PRA from 5.3 to 0.9 to 3.1 +/- 0.7 ng/ml.3 h (P less than 0.01). Results obtained with two lower doses of vasopressin (0.5 and 1.0 ng/kg.min) were generally similar to the responses observed during infusion at 2.0 ng/kg.min. Angiotensin II (5.0 ng/kg.min) suppressed PRA in all groups of dogs. These experiments demonstrate that the inhibition of renin secretion by acute administration of vasopressin in conscious dogs is prevented by total baroreceptor denervation, but not by denervation of the low pressure baroreceptors alone. These results suggest that the suppression of renin release by vasopressin is a reflex response resulting from activation of the high pressure baroreceptors.

Angiotensin II↗

PubMed1978

Histochemistry and acetylcholine receptor distribution in normal and denervated monkey extraocular muscles.

In monkey extraocular muscles (EOM), a battery of histochemical reactions delineates three muscle fiber types, coarse, fine, and granular. Normal EOM are compared with EOM denervated by intracranial oculomotor nerve section. The experimentally denervated EOM fibers did not show the constellation of histologic responses typical of denervated limb muscle, making a diagnosis of a denervation process in EOM muscle very difficult. Although the denervated fine and granular fibers (but not the coarse fibers) develop diffuse extrajunctional acetylcholine receptors (AChR) following experimental denervation, this is not a reliable criterion of denervation because not all of those fibers developed it and they did not show it beyond a 12-week period following nerve section; moreover, myopathic mechanisms have previously been shown capable of provoking diffuse extrajunctional AChR in limb-muscle fibers.

Acetylcholine↗

PubMed1987

Parasympathetic denervation supersensitivity in the rat iris sphincter muscle: an in vitro study.

Supersensitivity in chronically sympathectomized smooth muscle has long been studied, but little is known about chronically parasympathectomized smooth muscles. Iris is one of the few smooth muscle organs which can be parasympathetically denervated. We used rats because the denervation supersensitivity in the vas deferens has extensively been studied in this species. The rat was unilaterally ciliary-ganglionectomized. After 1-13 days, strips of the iris sphincter muscle obtained from denervated eye were tested for the sensitivity to acetylcholine (ACh), 5-hydroxytryptamine (5-HT) and K+. A significant increase in sensitivity to ACh and 5-HT was recognized as early as 1 day after the operation, and the sensitivity reached a maximum after 5-6 days, when ED50 values of ACh and 5-HT were reduced to approximately 1/28 and 1/4, respectively. The sensitivity to K+ was unaffected. When the sensitivity reached the maximum, the maximum responses to ACh, 5-HT and K+ were increased by 50%, 140% and 50%, respectively. The shift of the dose-response curve for bethanechol (BeCh) after denervation was comparable to that for ACh. Physostigmine shifted the curve for ACh, but did not shift that for BeCh either before or after denervation. Specific binding of 3H-quinuclidinyl benzylate tended to decrease after denervation, but the change was statistically not significant. These results indicate that the parasympathetic denervation supersensitivity in the rat iris sphincter involves a non-specific component, in addition to one specific to ACh and BeCh. The specific component seems to involve postsynaptic mechanisms.

Acetylcholine↗

PubMed2003

Beta adrenoceptor agonists, clenbuterol, and isoproterenol retard denervation atrophy in rat gastrocnemius muscle: use of 3-methylhistidine as a marker of myofibrillar degeneration.

The effects of beta adrenergic agonists, clenbuterol (2 mg/kg body weight/d) and isoproterenol (12 mg/kg body weight/d), in normal innervated and denervated rat gastrocnemius muscle were investigated. The daily administration of beta adrenergic agonists to normal innervated rats for a short period (7 d) resulted in the hypertrophy of gastrocnemius as confirmed from the measurement of total tissue protein contents. The development of denervation atrophy witnessed a stimulation in the expression of acid and alkaline phosphatases, pointing to an enhanced myofibrillar degeneration. An administration of beta adrenergic agonists inhibited the expression of raised levels of these enzymes in denervated muscle. A measurement of 3-methylhistidine in muscle revealed a loss of amino acid with the progress in the development of denervation atrophy. Serum and urine samples from denervated rats showed a progressive accumulation of 3-methylhistidine. Clenbuterol and isoproterenol treatment to these rats resulted in an inhibition of 3-methylhistidine accumulation. When 3-methylhistidine was used as a marker of myofibrillar degeneration, the results seemed to suggest that the degeneration of cyto-contractile apparatus accompanying denervation atrophy is attenuated in the presence of beta adrenergic agonists, implying that these sympathomimetic drugs are capable of reversing denervation atrophy in rat gastrocnemius.

Acid Phosphatase↗

PubMed2006

Remodeling of extracellular matrix protein, collagen by beta-adrenoceptor stimulation and denervation in mouse gastrocnemius muscle.

A chronic administration of isoproterenol hydrochloride (60 mg/kg body weight; 30 days) alters the collagen metabolism in denervated gastrocnemius muscle of mice. Hydroxyproline assay for collagen showed an increase in collagen content by 47%, 44%, and 61% in innervated gastrocnemius + drug, denervated control, and denervated + drug, respectively, in gastrocnemius muscles after 30 days of drug administration. Collagen proliferation is beta-agonist (isoproterenol) specific confirmed with the simultaneous administration of beta-antagonist propranolol (100 mg/kg body weight; 30 days). Van Gieson staining showed heavy collagen proliferation in the epimysium region of the muscle section and adventitia of blood vessels and some specialized regions. However, denervated gastrocnemius muscle represented a heavy collagen proliferation in the endomysium region, which also is probably responsible for extensive collagen proliferation in denervated muscle after drug administration. The SDS-PAGE of pepsin-soluble collagen revealed five bands from origin to the point of migration, gamma, beta1, beta2, alpha1, and alpha2. The SDS-PAGE of CNBr-treated pepsin-insoluble collagen pointed toward the more prominent remodeling of collagen metabolism in the beta-agonist-induced denervated gastrocnemius muscle after drug administration. From the present study, we can conclude that beta-agonist, isoproterenol hydrochloride, augments collagen proliferation in innervated as well as in denervated gastrocnemius muscle.

Adrenergic beta-Agonists↗