Contraction Threshold Research Articles

Effects of chronic treatment with statins and fenofibrate on rat skeletal muscle: a biochemical, histological and electrophysiological study

Skeletal muscle injury by hypolipidemic drugs is not fully understood. An extensive analysis of the effect of chronic treatment with fluvastatin (5 mgkg(-1) and 20 mgkg(-1)), atorvastatin (10 mgkg(-1)) and fenofibrate (60 mgkg(-1)) on rat skeletal muscle was undertaken. Myoglobinemia as sign of muscle damage was measured by enzymatic assay. Histological and immunohistochemical techniques were used to estimate muscle integrity and the presence of aquaporin-4, a protein controlling water homeostasis. Electrophysiological evaluation of muscle Cl(-) conductance (gCl) and mechanical threshold (MT) for contraction, index of intracellular calcium homeostasis, was performed by the two-intracellular microelectrodes technique. Fluvastatin (20 mgkg(-1)) increased myoglobinemia. The lower dose of fluvastatin did not modify myoglobinemia, but reduced urinary electrolytes, suggesting direct effects on renal function. Atorvastatin also increased myoglobinemia, with slight effects on urinary parameters. No treatment caused any histological damage to muscle or modification in the number of fibres expressing aquaporin-4. Either fluvastatin (at both doses) or atorvastatin reduced sarcolemma gCl and changed MT. Both statins produced slight effects on total cholesterol, suggesting that the observed modifications occur independently of HMGCoA-reductase inhibition. Fenofibrate increased myoglobinemia and decreased muscle gCl, whereas it did not change the MT, suggesting a different mechanism of action from the statins. This study identifies muscle gCl and MT as early targets of drugs action that may contribute to milder symptoms of myotoxicity, such as muscle cramps, while the increase of myoglobinemia is a later phenomenon.

EFFECT OF LOW‐VOLTAGE ELECTRICAL STIMULATION ON ANGIOGENIC GROWTH FACTORS IN ISCHAEMIC RAT SKELETAL MUSCLE

1. Low-voltage electrical stimulation (LVES) in skeletal muscle at a level far below the threshold of muscle contraction has been reported to promote local angiogenesis. However, the mechanism underlying the promotion of local angiogenesis by LVES has not been fully elucidated. In the present study, we evaluated whether angiogenic factors, such as vascular endotherial growth factor (VEGF), hepatocyte growth factor (HGF) and fibroblast growth factor (FGF), as well as other disadvantageous factors, such as inflammation (interleukin (IL)-6) and hypoxia (hypoxia-inducible factor (HIF)-1alpha), contribute to the local angiogenesis produced by LVES. 2. We completely excised bilateral femoral arteries of male Sprague-Dawley rats. After the operation, electrodes were implanted onto the centre of the fascia of the bilateral tibialis anterior (TA) muscles, tunnelled subcutaneously and exteriorized at the level of the scapulae. The right TA muscles of rats were stimulated continuously at a stimulus frequency of 50 Hz, with a 0.1 V stimulus strength and no interval, for 5 days. The left TA muscles served as controls. 3. We found that both VEGF and HGF protein were significantly increased by LVES in stimulated muscles compared with control. The VEGF level of the LVES group was 89.10 +/- 17.19 ng/g, whereas that of the control group was 65.07 +/- 12.88 ng/g, as determined by ELISA (P < 0.05). The HGF level of the LVES and control groups was 8.52 +/- 1.96 and 5.80 +/- 2.14 ng/g, respectively (P < 0.05). In contrast, there was no difference in FGF, IL-6 and HIF-1alpha between the LVES and control groups. 4. These results suggest that LVES in a hindlimb ischaemia model of rats increases not only VEGF, but also HGF, production, which may be the main mechanism responsible for the angiogenesis produced by LVES.

The functional effects of a c‐kit tyrosine inhibitor on guinea‐pig and human detrusor

To describe the effect of a specific c-kit receptor inhibitor (imatinib mesylate) on human detrusor strips in vitro and guinea-pig cystometry in vivo, and to show histological data suggesting differences in the distribution of interstitial cells of Cajal (ICC)-like cells in 'normal' and overactive human detrusor, as these cells have been identified as possible mediators of spontaneous activity and excitability in bladder smooth muscle. Specimens of human detrusor were stained immunohistochemically with a c-kit antibody. Human detrusor strips were mounted in a superfused organ-bath apparatus, and smooth muscle contraction was evoked with carbachol and electrical field stimulation in the presence and absence of imatinib mesylate. Also, guinea-pig urodynamic studies were conducted before and after i.v. administration of imatinib mesylate, and changes in bladder variables and spontaneous activity were recorded. Imatinib mesylate (10(-6)M) inhibited evoked smooth muscle contraction and spontaneous activity in overactive human detrusor, with less effect on normal human tissue. Imatinib mesylate (10(-5)M) improved bladder capacity, compliance, voided volumes, urinary frequency, and reduced contraction thresholds and spontaneous activity during guinea-pig cystometry. c-kit labelling showed significantly more ICC-like cells in overactive human detrusor than in normal specimens. c-kit receptor blockers have inhibitory effects on guinea-pig and overactive human detrusor, possibly via c-kit receptors on bladder ICC-like cells. This and the possibility that there are more ICC-like cells in overactive bladder suggest that the c-kit receptor may provide a novel target for treating detrusor overactivity.

Effect of partial bladder outlet obstruction on detrusor compliance, excitability and contractility in rats

Partial bladder outlet obstruction (PBOO) is believed to change the functions of the detrusor, and can lead to an overactive detrusor (OD). The aim of this study was to investigate changes in bladder compliance, excitability and contractility after PBOO in rats. PBOO was performed for 6 weeks in 20 Wistar rats, 13 of which (OD group) had an OD and seven of which (non-OD group) did not. Simultaneously, 10 rats that underwent sham operations (control group) were also studied. Bladder compliance and cystometric capacity were identified in vivo, but bladder compliance was detected without elimination of bladder capacity. Isolated bladder smooth muscle strip (BSMS) was dissected to determine excitability and contractility. After 6 weeks of PBOO, cystometric capacity and compliance were significantly higher than those in the control group. Compliance was 0.170+/-0.029 and 0.149+/-0.042 ml/cmH2O in the OD and non-OD groups, respectively, compared to 0.037+/-0.017 ml/cmH2O in the control group. The corresponding cystometric capacities were 3.66+/-0.490, 3.08+/-0.590 and 1.14+/-0.225 ml. The excitability in the OD group increased significantly compared to that in the non-OD and control groups. The tension threshold for BSMS contraction was lower in the OD group, and BSMS contracted more frequently at the same tension. The contractility of the BSMS in the OD group decreased significantly compared to that in the non-OD and control groups. PBOO can cause a higher cystometric capacity and compliance. After PBOO, there is a chance that an OD may develop. When this occurs, the detrusor excitability increases and contractility decreases.

Central Acute D2 Stimulation Worsens Bladder Function in Patients With Mild Parkinson’s Disease

The different roles of D1 and D2 dopamine receptors in LUT behavior have been demonstrated in animal studies. In particular D2 selective agonists and D1 selective antagonists seem to produce a reduction of the bladder capacity in conscious rats. This finding has never been confirmed in human studies. Thus, in this study we investigated the role of D1 and D2 agonists/antagonists on LUT behavior in patients with PD. A total of 87 patients with mild PD were evaluated. Patients were evaluated with urodynamic studies (cystometry followed by a pressure flow study with perineal floor electromyography) performed in off status and after oral administration of 250 mg of LD. In 70 patients a third urodynamic evaluation was conducted in one of the following conditions: after simultaneous administration of 250 mg oral LD and 60 or 120 mg oral domperidone (D2 peripheral antagonist); after simultaneous administration of 250 mg oral LD and 25, 50 or 150 mg intramuscular L-sulpiride (D2 central and peripheral antagonist). Several urodynamic parameters were evaluated and results obtained in different conditions compared. LD alone worsened detrusor overactivity: in particular, a reduction of first urinary sensation, involuntary detrusor contraction threshold (reflex volume) and bladder capacity was observed. L-sulpiride (central and peripheral D2 antagonist) coadministration counteracted the worsening in a dose dependent manner. Domperidone (peripheral D2 antagonist) coadministration failed to determine the same counteraction. According to our results, a central acute D2 stimulation seems to be responsible of a reduction of bladder capacity with worsening of detrusor overactivity in patients with mild PD.

Acute effects of adrenergic agents on post-defibrillation arrest time in a cultured heart model

Possible drug interactions with electrical defibrillation were examined. We tested the hypothesis that adrenergic agents (epinephrine, norepinephrine, isoproterenol) and a calcium channel blocker (verapamil), when applied acutely, alter the duration of arrest following a defibrillator shock. A secondary hypothesis (based on observations) was that the drugs alter the occurrence of changes to normal rhythms following the shock. Dissociated heart cells from 10-day chicken embryos were cultured to form spherical aggregates and plated in petri dishes. In the experiments, the spheres were paced at 0.75 V/cm above contraction threshold, and a biphasic defibrillator shock was applied for 1 ms at 46 V/cm. The arrest time and occurrence of rhythm changes were recorded. The adrenergic agents shortened the duration of arrest following a defibrillator shock, while the calcium channel blocker lengthened the arrest time. Comparisons with the control proportion of double beats showed no significant change with the adrenergic agents and a decrease with verapamil.

Physiologic variables that predict the outcome of treatment for fecal incontinence

Identification of physiologic factors that predict response to fecal incontinence therapy would be helpful in choosing the optimal treatment and advising patients on the likelihood of a successful outcome. However, few physiologic parameters have been consistently identified as important in predicting response to either biofeedback or surgery. The process of isolating these factors has been hampered by heterogeneity in the definition of fecal incontinence, lack of consensus on what constitutes a successful outcome, lack of follow-up data, variations in the way “standard” treatments are implemented, and lack of properly powered randomized controlled trials. Among the physiologic variables that studies have generally found to be predictive of successful outcomes in biofeedback treatment are the threshold for external anal sphincter contraction after treatment, the inclusion of sensory training in treatment, and a reduction in volume for the first sensation after treatment. Factors that have not been found to be important in predicting outcome following biofeedback retraining include the duration of fecal incontinence, pudendal nerve damage, patient age, symptom severity, pretreatment anal canal pressures, and results of anal ultrasonography. The presence of some degree of anorectal sensation is the only preoperative assessment that has been found to be predictive of response to surgical therapy. It is recommended that outcome measures for fecal incontinence be more clearly defined, that future biofeedback studies elaborate the predictive value of pretreatment anorectal sensation and the response to sensory retraining, and that postsurgical measurements such as anal squeeze pressure and sphincter length be taken into account.

Spasmogenic action of endothelin-1 on isolated equine pulmonary artery and bronchus.

There is currently little published information about the effects of endothelin-1 (ET-1), a potent endogenous spasmogen of vascular and airway smooth muscle, on pulmonary vasculature and airways or which ET receptor subtypes mediate ET-1-induced vasoconstrictive and bronchoconstrictive action in the horse. To investigate the effect of endothelin-1 (ET-1) on smooth muscle from isolated equine pulmonary artery and bronchus. In addition, the roles of ETA and ETB receptors in ET-1 mediated contraction in these tissues were assessed. The force generation of ring segments from pulmonary arteries or third-generation airways (obtained from horses subjected to euthanasia for orthopaedic reasons) were studied in an organ bath at 37 degrees C in response to exogenous endothelin and selective endothelin A (BQ123) or B receptor (BQ788) antagonists. ET-1 produced concentration-dependent contractions of the equine pulmonary artery and bronchus. The threshold for contraction was 10(-10) and 10(-9) mol/l ET-1 for pulmonary artery and bronchus, respectively. The maximal contraction induced by the highest ET-1 concentration (10(-7) mol/l) was 173 and 194% of the contraction obtained with 100 mmol/l KCl in pulmonary artery and bronchus, respectively. ET-1 potency was 25 times greater in equine pulmonary artery than in equine bronchus (concentration of ET-1 producing 50% of maximal contraction [EC50] = 5.6 10(-9) mol/l and 2.2 10(-8) mol/l, respectively). In pulmonary artery, ET-1 induced contractions were significantly inhibited by the ETA receptor antagonist BQ123 (1 micromol/l; dose-response curve to ET-1 was shifted to the right by 5.4-fold), but not by the ETB antagonist BQ788. In bronchus, dose-responses curves to ET-1 were shifted to the right by BQ123 (1 micromol/l; 2.5-fold), but not by BQ788 (1 micromol/l). In the presence of both antagonists, the dose-response curve to ET-1 was shifted to the right by 4.5-fold. These functional studies demonstrate that ET-1 is a potent spasmogen of equine third generation pulmonary artery and bronchus, and that contractions are mediated via ETA receptors in the former and both ETA and ETB receptors in the latter. Endothelin receptor antagonists may have potential for treating equine pulmonary hypertension or bronchoconstriction.

Motor cortex stimulation in patients with post-stroke pain: Conscious somatosensory response and pain control

We analyzed the conscious sensory responses to cortical stimulation of 31 patients with post-stroke pain who underwent motor cortex stimulation (MCS) therapy. During surgery for electrode placement, a sensory response (tingle projected to a localized peripheral area) was elicited by high-frequency stimulation (50 Hz) in 23 (84%) from the somatosensory cortex, and in 16 (52%) from the motor cortex without muscle contraction. Unpleasant painful sensation was induced or their original pain was exacerbated in 12 patients (39%) when the somatosensory cortex was stimulated and in two (6%) when the motor cortex was stimulated. Somatosensory responses were induced in eight (25%) even by low-frequency stimulation (1–f the motor cortex at an intensity below the threshold for muscle contraction. In contrast, among 20 nonpain patients who underwent a similar procedure for cortical mapping in epilepsy or brain tumor surgery, a sensory response was produced by high-frequency stimulation in only eight (40%; p < 0.02) from the somatosensory cortex and four (20%; p < 0.03) from the motor cortex. Pain sensation was not induced by stimulation of the somatosensory cortex (p < 0.002) or motor cortex in any of these patients. In addition, none of these patients reported a sensory response to low-frequency stimulation. In both of the two post-troke pain patients who reported abnormal pain sensation in response to stimulation of the motor cortex, MCS failed to control their post-stroke pain. These findings imply that the sensitivity of the perceptual system even to activity of the motor cortex is heightened in post-stroke pain patients, which can sometimes hinder pain control by MCS.

Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1.

A preclinical screening for prompt-to-use drugs that are safer than steroids and beneficial in Duchenne muscular dystrophy was performed. Compounds able to reduce calcium-induced degeneration (taurine or creatine 10% in chow) or to stimulate regeneration [insulin-like growth factor-1 (IGF-1); 50 or 500 microg/kg s.c.] were administered for 4 to 8 weeks to mdx mice undergoing chronic exercise on a treadmill, a protocol to worsen dystrophy progression. alpha-Methyl-prednisolone (PDN; 1 mg/kg) was used as positive control. The effects were evaluated in vivo on forelimb strength and in vitro electrophysiologically on the macroscopic chloride conductance (gCl), an index of degeneration-regeneration events in mdx muscles, and on the mechanical threshold, a calcium-sensitive index of excitation-contraction coupling. The exercise produced a significant weakness and an impairment of gCl, by further decreasing the already low value of degenerating diaphragm (DIA) and fully hampering the increase of gCl typical of regenerating extensor digitorum longus (EDL) mdx muscle. The already negative voltage threshold for contraction of mdx EDL was also slightly worsened. Taurine > creatine > IGF-1 counteracted the exercise-induced weakness. The amelioration of gCl was drug- and muscle-specific: taurine was effective in EDL, but not in DIA muscle; IGF-1 and PDN were fully restorative in both muscles, whereas creatine was ineffective. An acute effect of IGF-1 on gCl was observed in vitro in untreated, but not in IGF-1-treated exercised mdx muscles. Taurine > PDN > IGF-1, but not creatine, significantly ameliorated the negative threshold voltage values of the EDL fibers. The results predict a potential benefit of taurine and IGF-1 for treating human dystrophy.

Smooth muscle cells contract in response to fluid flow via a Ca2+-independent signaling mechanism.

Smooth muscle cells (SMC) are exposed to fluid shear stress because of transmural (interstitial) flow across the arterial wall. This shear stress may play a role in the myogenic response and flow-mediated vasomotion. We, therefore, examined the effects of fluid flow on contraction of rat aortic SMC. SMC that had been serum-starved to induce a contractile phenotype were plated on quartz slides and exposed to controlled shear stress levels in a flow chamber. The area of the cells was quantified, and reduction in the cell area was reported as contraction. At 25 dyn/cm(2), significant area reduction was apparent 3 min after the onset of flow and exceeded 30% at 30 min. At 1 dyn/cm(2), significant contraction was not observed at 30 min. The threshold for significant shear-induced contraction appeared to be 11 dyn/cm(2). The signal transduction mechanism was studied at 25 dyn/cm(2). Intracellular calcium was imaged by using the calcium-sensitive fluorescent dye fura 2-AM. There was no detectable change in intracellular calcium during 10 min of exposure to shear stress, even though the cells displayed a significant calcium response to thapsigargin, calcium ionophore, and KCl. Further studies using pathway inhibitors provided evidence that the most important signal transduction pathway mediating calcium-independent contraction in response to fluid flow is the Rho-kinase pathway, although there was a suggestion that protein kinase C plays a secondary role.

Muscle Reinnervation with Delayed or Immediate Transplant of Embryonic Ventral Spinal Cord Cells into Adult Rat Peripheral Nerve

Muscle denervation is common in various neuromuscular diseases and after trauma. It induces skeletal muscle atrophy. Only muscle reinnervation leads to functional recovery. In previous studies, denervated adult rat muscles were rescued by transplantation of embryonic day 14-15 (E14-15) ventral spinal cord cells into a nearby peripheral nerve. In the present study, changes were made in the environment into which the cells were placed to test whether reinnervation was improved by: 1) prior nerve degeneration, induced by sciatic nerve transection 1 week before cell transplantation; 2) transplantation of 1 million versus 5 million cells; 3) addition of nerve growth factor (NGF) to the transplant. Ten weeks after cell transplantation, axons had grown from all of the transplants. The numbers of myelinated axons that regenerated into the tibial, medial (MG), and lateral gastrocnemius-soleus (LGS) nerves were similar across treatments. The mean diameters of large LGS axons (>6 microm) were significantly larger with nerve degeneration before transplantation. The mean diameters of MG and LGS axons were significantly larger with transplantation of 1 million versus 5 million cells. Silver-stained experimental and control lateral gastronemius (LG) muscles showed axons that terminated at motor end plates. Nodal and terminal sprouts were more common in reinnervated muscles (45-63% of all end plates) than in control muscles (10%). Electrical stimulation of the transplants induced weak contractions in 39 of 47 MG muscles (83%) and 33 of 46 LG muscles (72%) but at higher voltages than needed to excite control muscles. The threshold for MG contraction was lower with transplantation of 1 million cells, while LG thresholds were lower without NGF. The cross-sectional area of whole LG muscles was significantly larger with cell transplantation (immediate or delayed) than with media alone, but all of these muscle areas were reduced significantly compared with control muscle areas. These data suggest that delayed transplantation of fewer cells without NGF assists regeneration of larger diameter axons and prevents some muscle atrophy.

Intravesical Capsaicin Versus Resiniferatoxin In Patients With Detrusor Hyperreflexia: A Prospective Randomized Study

Capsaicin and resiniferatoxin (Sigma Chemical Co., St. Louis, Missouri) administered intravesically are attractive options for treating detrusor hyperreflexia. Because the 2 agents differ in chemical structure and relative potency, possible differences in their clinical and urodynamic effects were investigated in this prospective comparative study. A group of 24 spinal cord injured patients with refractory detrusor hyperreflexia were randomly assigned to receive a single dose of 2 mM. capsaicin in 30 ml. ethanol plus 70 ml. 0.9% sodium chloride or 100 nM. resiniferatoxin in 100 ml. 0.9% sodium chloride. Dwell time was 40 minutes with urodynamic monitoring. Urodynamics were performed at baseline before treatment, and after followups of 30 and 60 days. The frequency of daily catheterizations, incontinence episodes and side effects was recorded. There was no significant urodynamic or clinical improvement in the capsaicin arm at 30 and 60 days of followup. In the resiniferatoxin arm the mean uninhibited detrusor contraction threshold plus or minus standard deviation increased from 176 +/- 54 to 250 +/- 107 ml. at 30 days (p <0.05) and to 275 +/- 98 ml. at 60 days (p <0.01). Mean maximum bladder capacity increased from 196 +/- 75 to 365 +/- 113 ml. at 30 days (p <0.001) and to 357 +/- 101 ml. at 60 days (p <0.001). Daily catheterizations and incontinent episodes were significantly decreased at 30 and 60 days of followup. Autonomic dysreflexia, limb spasms, suprapubic discomfort and hematuria developed in most patients who received capsaicin but in none who received resiniferatoxin. Intravesical administration of resiniferatoxin is superior to that of capsaicin in terms of urodynamic results and clinical benefits in spinal cord injured patients and it does not cause the inflammatory side effects associated with capsaicin.

Sensory retraining is key to biofeedback therapy for formed stool fecal incontinence

Biofeedback is a nonsurgical treatment that reportedly produces good results in 65-75% of fecally incontinent patients. However, previous studies have not ruled out nonspecific treatment effects. It is also unknown whether biofeedback works primarily by improving the strength of the striated pelvic floor muscles or by improving the rectal perception. We aimed to 1) evaluate the efficacy of biofeedback in formed-stool fecal incontinence, 2) assess the relative contribution of sensory and strength retraining to biofeedback outcomes, and 3) identify patient characteristics that predict a good response to treatment. Twenty-four patients with frequent (at least once a week) solid-stool incontinence were provided with three to four biofeedback sessions. They were taught to squeeze in response to progressively weaker rectal distentions. Patients were re-evaluated by anorectal manometry and symptom diary 3 months after completing training and by diary and interview 6-12 months after training. Seventeen (71%) were classified responders; 13 became continent and four reduced incontinence frequency by at least 75%. Clinical improvements were maintained at 12-month follow-up. At 3-month follow-up, responders had significantly lower thresholds for perception of rectal distention and for sphincter contraction, but squeeze pressures did not significantly differ from those of nonresponders. Baseline measures that predicted a favorable response were sensory threshold (50 ml or less), urge threshold (100 ml or less), lower threshold for sphincter contraction, and lower threshold for the rectoanal inhibitory reflex; neither anal squeeze pressure nor severity of incontinence predicted treatment outcome. In solid-stool fecal incontinence biofeedback training effects are robust and seem not to be explained by expectancy or nonspecific treatment effect. Sensory retraining appears to be more relevant than strength training to the success of biofeedback.

Sensory retraining is key to biofeedback therapy for formed stool fecal incontinence

OBJECTIVES: Biofeedback is a nonsurgical treatment that reportedly produces good results in 65–75% of fecally incontinent patients. However, previous studies have not ruled out nonspecific treatment effects. It is also unknown whether biofeedback works primarily by improving the strength of the striated pelvic floor muscles or by improving the rectal perception. We aimed to 1) evaluate the efficacy of biofeedback in formed-stool fecal incontinence, 2) assess the relative contribution of sensory and strength retraining to biofeedback outcomes, and 3) identify patient characteristics that predict a good response to treatment. METHODS: Twenty-four patients with frequent (at least once a week) solid-stool incontinence were provided with three to four biofeedback sessions. They were taught to squeeze in response to progressively weaker rectal distentions. Patients were re-evaluated by anorectal manometry and symptom diary 3 months after completing training and by diary and interview 6–12 months after training. RESULTS: Seventeen (71%) were classified responders: 13 became continent and four reduced incontinence frequency by at least 75%. Clinical improvements were maintained at 12-month follow-up. At 3-month follow-up, responders had significantly lower thresholds for perception of rectal distention and for sphincter contraction, but squeeze pressures did not significantly differ from those of nonresponders. Baseline measures that predicted a favorable response were sensory threshold (50 ml or less), urge threshold (100 ml or less), lower threshold for sphincter contraction, and lower threshold for the rectoanal inhibitory reflex; neither anal squeeze pressure nor severity of incontinence predicted treatment outcome. CONCLUSIONS: In solid-stool fecal incontinence biofeedback training effects are robust and seem not to be explained by expectancy or nonspecific treatment effect. Sensory retraining appears to be more relevant than strength training to the success of biofeedback.

Effect of Burst-Mode Transcutaneous Electrical Nerve Stimulation on Peripheral Vascular Resistance

Based on changes in skin temperature alone, some authors have proposed that postganglionic sympathetic vasoconstrictor fibers can be stimulated transcutaneously. Our goal was to determine the effects of low-frequency (2 bursts per second), burst-mode transcutaneous electrical nerve stimulation (TENS) on calf vascular resistance, a more direct marker of sympathetic vasoconstrictor outflow than skin temperature, in subjects with no known pathology. Fourteen women and 6 men (mean age=31 years, SD=13, range=18-58) participated in this study. Calf blood flow, arterial pressure, and skin temperature were measured while TENS was applied over the common peroneal and tibial nerves. Blood flow immediately following stimulation was not affected by TENS applied just under or just above the threshold for muscle contraction. Transcutaneous electrical nerve stimulation applied at 25% above the motor threshold caused a transient increase in calf blood flow. Regardless of stimulation intensity, TENS had no effect on arterial pressure; therefore, calf vascular resistance decreased only during the trial that was 25% above the motor threshold. Regardless of stimulation intensity, TENS failed to alter dorsal or plantar skin temperature. These results demonstrate that the effects of TENS on circulation depend on stimulation intensity. When the intensity was sufficient to cause a moderate muscle contraction, a transient, local increase in blood flow occurred. Cooling of the dorsal and plantar skin occurred in both the stimulated and control legs, most likely because skin temperature acclimatized to ambient room temperature, rather than because of any effect of TENS on circulation. The data, therefore, call into question the idea that postganglionic sympathetic efferent fibers are stimulated when TENS is applied at clinically relevant intensities to people without symptoms of cardiovascular or neuromuscular pathology.

The effect of varying frequency and intensity of transcutaneous electrical nerve stimulation on secondary mechanical hyperalgesia in an animal model of inflammation

For years, transcutaneous electrical nerve stimulation (TENS) has been used clinically for the treatment of many types of pain. Although there have been many studies conducted on the efficacy of TENS in the clinical setting, the results are conflicting. The purpose of our investigation was to determine the effect of varying frequency and intensity of TENS on secondary mechanical hyperalgesia induced by acute joint inflammation. Male Sprague-Dawley rats were injected with a mixture of 3% carrageenan and 3% kaolin (100 μL in 0.9% sterile saline) into the joint cavity of one knee. The response threshold to mechanical stimuli was determined before inflammation of the knee joint; 4 hours after inflammation; immediately after the administration of TENS (approximately 5 hours after inflammation); and at 8, 12, and 24 hours after inflammation. TENS was applied to the inflamed knee joint at either high (100 Hz) or low (4 Hz) frequency and at either sensory or motor intensity. Sensory intensity was just below the threshold for motor contraction, and motor intensity was 2 × threshold for motor contraction. Either low- or high-frequency TENS is equally successful in reducing secondary mechanical hyperalgesia. Similarly, either sensory- or motor-intensity TENS equally reduces secondary mechanical hyperalgesia. Thus, selection of TENS should be based on patient comfort and symptoms for relief of secondary mechanical hyperalgesia.

Alteration of excitation‐contraction coupling mechanism in extensor digitorum longus muscle fibres of dystrophic mdx mouse and potential efficacy of taurine

No clear data is available about functional alterations in the calcium-dependent excitation-contraction (e-c) coupling mechanism of dystrophin-deficient muscle of mdx mice. By means of the intracellular microelectrode "point" voltage clamp method, we measured the voltage threshold for contraction (mechanical threshold; MT) in intact extensor digitorum longus (EDL) muscle fibres of dystrophic mdx mouse of two different ages: 8 - 12 weeks, during the active regeneration of hind limb muscles, and 6 - 8 months, when regeneration is complete. The EDL muscle fibres of 8 - 12-week-old wildtype animals had a more negative rheobase voltage (potential of equilibrium for contraction- and relaxation-related calcium movements) with respect to control mice of 6 - 8 months. However, at both ages, the EDL muscle fibres of mdx mice contracted at more negative potentials with respect to age-matched controls and had markedly slower time constants to reach the rheobase. The in vitro application of 60 mM taurine, whose normally high intracellular muscle levels play a role in e-c coupling, was without effect on 6 - 8-month-old wildtype EDL muscle, while it significantly ameliorated the MT of mdx mouse. HPLC determination of taurine content at 6 - 8 months showed a significant 140% rise of plasma taurine levels and a clear trend toward a decrease in amino acid levels in hind limb muscles, brain and heart, suggesting a tissue difficulty in retaining appropriate levels of the amino acid. The data is consistent with a permanent alteration of e-c coupling in mdx EDL muscle fibres. The alteration could be related to the proposed increase in intracellular calcium, and can be ameliorated by taurine, suggesting a potential therapeutic role of the amino acid.

Diet, Body Size, and Landscape Use among Holocene People in the Southern Cape, South Africa

Diet, Body Size, and Landscape Use among Holocene People in the Southern Cape, South Africa

Changes in the Ca2+-activation characteristics of demembranated rat single muscle fibres after prolonged incubation at room temperature in the presence and absence of DTT and protease inhibitors.

Prolonged incubation (24 h) of chemically skinned rat muscle preparations in rigor solutions at room temperature and in the absence of reducing agents and protease inhibitors modified the Ca2+-activation characteristics of the contractile machinery. In the absence of reducing agents and protease inhibitors, the contraction threshold for incubated fibres was shifted to lower Ca2+ concentrations and the steepness of the steady-state force-pCa (-log10)[Ca2+]) curve was decreased compared to that of control muscle fibres. Mean myosin ATPase activity under these conditions was significantly lowered by a factor of 2.7. Fibres incubated in the presence of 10 mM dithiothreitol (DTT) and protease inhibitors (100 microM pepstatin A/200 microM leupeptin) produced a maximum Ca2+-activated force per cross-sectional area that compared favourably with that of freshly dissected muscle fibres and there were no changes in the other contractile activation characteristics. Intermediate responses were obtained when fibres were incubated in the presence of either DTT or protease inhibitors. MgATPase activities of incubated preparations increased significantly following the addition of protease inhibitors and/or DTT to the incubation medium. Taken together, these results suggest that in the presence of DTT and protease inhibitors, most contractile properties are maintained at levels seen in fresh mechanically skinned fibres. The extended viability of this preparation and its closely related properties with fresh muscle fibres make it a useful model for experiments requiring longer term incubations with biological agents.