Caffeine improves neuromuscular function during maximal dynamic exercise

Introduction: In this study we tested the hypothesis that caffeine supplementation improves neuromuscular function, which has both nutritional and clinical relevance. Methods: Fourteen male subjects (mean ± SD: 23.8 ± 2.8 years) volunteered in a double‐blind, repeated‐measures study with placebo (PLA) or caffeine (CAFF) (6 mg kg^?1). Maximal voluntary isometric contractions (MVCs), evoked maximal twitch, and maximal isokinetic contractions during elbow flexion were assessed. Mechanical and electromyographic (EMG) signals from the biceps brachii muscle were recorded, and muscle fiber conduction velocity (CV) was calculated to evaluate changes in the muscle force–velocity relationship and muscle fiber recruitment. Results: The torque–angular velocity curve was enhanced after CAFF supplementation. This was supported by a concomitant increase of CV values (8.7% higher in CAFF). Conclusions: Caffeine improves muscle performance during short‐duration maximal dynamic contractions. The concomitant improvement of mean fiber CV supports the hypothesis of an effect of caffeine on motor unit recruitment. Muscle Nerve, 2011.     

Linearity and reliability of the mechanomyographic amplitude versus dynamic torque relationships for the superficial quadriceps femoris muscles

The purpose of this investigation was to examine the linearity and reliability of the mechanomyographic (MMG) amplitude versus dynamic torque relationships for the vastus lateralis (VL), rectus femoris (RF), and vastus medialis (VM) muscles. Nine healthy men and 11 healthy women performed submaximal to maximal, concentric, isokinetic muscle actions of the leg extensors at 30° s^?1 on two occasions. Surface MMG signals were detected from the VL, RF, and VM of the dominant thigh during both trials. The ranges of the coefficients of determination for the MMG amplitude versus dynamic torque relationships were 0.01–0.94 for the VL, 0.01–0.84 for the RF, and 0.19–0.96 for the VM. The intraclass correlation coefficients for the linear MMG amplitude versus torque slope coefficients were 0.823 (VL), 0.792 (RF), and 0.927 (VM). These results indicate that, when analyzed for individual subjects, the MMG amplitude versus dynamic torque relationships demonstrated inconsistent linearity. When using MMG in the clinical setting, dynamic muscle actions of the superficial quadriceps femoris muscles do not appear to be appropriate for assessing changes in muscle function during strength training. Muscle Nerve, 2009     

Mechanomyographic and electromyographic responses to eccentric and concentric isokinetic muscle actions of the biceps brachii

The purpose of the present investigation was to examine the effects of forearm angular velocity on the mechanomyographic (MMG) and electromyographic (EMG) responses to eccentric and concentric isokinetic muscle actions. Ten adult male volunteers (mean ± SD age = 23 ± 2 years) performed maximal eccentric and concentric muscle actions of the forearm flexors at 30°, 90°, and 150° s⁻¹. There was no significant (P > 0.05) velocity-related change in peak torque (PT) for the eccentric muscle actions, but there was a significant (P < 0.05) decrease in PT for the concentric muscle actions. For the eccentric and concentric muscle actions, there was a significant (P < 0.05) velocity-related increase in MMG amplitude. There was no significant (P < 0.05) change in EMG amplitude across velocity for the eccentric or concentric muscle actions. The results indicated velocity-related dissociations among the PT, MMG, and EMG responses to maximal eccentric and concentric isokinetic muscle actions. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1438–1444, 1998     

Assessment of musculo‐articular and muscle stiffness in young and older men

Introduction: The aim of this cross‐sectional study was to concurrently assess musculo‐articular stiffness (MAS) and muscle stiffness (MS) of the knee extensors in younger and older individuals. Methods: Fourteen young (22.1 ± 3.0 years old) and 12 older (65.4 ± 5.7 years old) men were tested for maximal voluntary contraction (MVC), rate of torque development (RTD), muscle thickness, MAS, and MS of knee extensors. Results: MVC, RTD, and muscle thickness were higher in the younger group (288.6 vs. 194.3 Nm, 1319.5 vs. 787.0 Nm s^?1, 23.1 vs. 17.7 mm, respectively, P < 0.05). MAS normalized to the load supported (30% of MVC) was not different between groups (87.9 vs. 88.5 Nm^?1kg^?1), whereas the older group exhibited a higher level of normalized MS (23.2 vs. 18.6 Nm^?1kg^?1, P < 0.05). Conclusions: Determinants of MS have been highlighted along with their role in elevated MS. The unaltered level of MAS, which is functionally important in an aging population, might be achieved through a decrease in tendon stiffness. Muscle Nerve 46: 559–565, 2012     

Wavelet analysis of quadriceps power spectra and amplitude under varying levels of contraction intensity and velocity

Introduction: We investigated the effect of contraction intensity [100%, 75%, 50%, and 25% maximum voluntary contraction (MVC)] and movement velocity (50°, 100°, 200°, and 400°/s) on surface electromyography root mean square amplitude (SEMG_RMS) and median frequency (SEMG_MDF) of rectus femoris (RF), vastus lateralis (VL), and vastus medialis (VM). Methods: SEMGs during knee extension were resolved into their respective frequencies using wavelet transformations. Results: RF, VL, and VM muscles displayed increased SEMG_MDF as contraction intensity increased from 25% to 50% MVC and from 75% to 100% MVC, and each muscle displayed its own unique frequency shifting patterns. The SEMG_MDF was not influenced by movement velocity. SEMG_RMS increased in all 3 muscles as contraction intensity increased and was influenced by movement velocity, with the highest values observed at 400° and 200°/s. Conclusions: We infer that increasing contraction intensity facilitates greater recruitment of fast‐twitch muscle fibers, but there are differing responses in RF, VL, and VM muscles. Muscle Nerve 50 : 844–853, 2014     

Age‐related fatigue resistance in the knee extensor muscles is specific to contraction mode

The question of whether skeletal muscle fatigue is preserved or enhanced in older adults is a point of controversy. Disparate findings may be attributed to differences in subject population and study protocols, including contraction mode. The purpose of this study was to test the hypotheses that healthy older (65–80 years of age, 8 males and 8 females) adults who were matched to young adults (21–35 years of age; 8 males and 8 females) with similar physical activity levels would: (1) fatigue less during isometric knee extensor (KE) contractions, but (2) would show similar fatigue during dynamic KE contractions performed at 120° s^?1. Fatigue was induced with 4 minutes of intermittent, isometric, or dynamic maximal voluntary contractions, performed on separate days. Electrically stimulated contractions were used to evaluate central activation during both fatigue protocols. Older subjects maintained a higher percentage of baseline maximum voluntary contraction (MVC) torque than young subjects during isometric contractions (mean ± SE: 71 ± 3% and 57 ± 3%, respectively, P < 0.01). In contrast, there was no difference between age groups in torque maintenance during dynamic contractions (43 ± 3% and 44 ± 3%, respectively, P = 0.86). For both groups, changes in electrically stimulated and voluntary contractions followed similar trends, suggesting that central activation did not play a role in the age‐related differences in fatigue. Fatigue during the isometric protocol was associated with fatigue during the dynamic protocol in the young group only (r = 0.62, P = 0.01), suggesting that distinct mechanisms influence fatigue during isometric and dynamic contractions in older adults. Muscle Nerve 39: 692–702, 2009     

Variability and distribution of muscle strength and its determinants in humans

Introduction: Inter‐individual variability in measurements of muscle strength and its determinants was identified to: (1) produce a normative data set describing the normal range and (2) determine whether some measurements are more informative than others when evaluating inter‐individual differences. Methods: Functional and morphological characteristics of the vastus lateralis were measured in 73 healthy, untrained adult men. Results: Inter‐individual variability (coefficient of variation) was greater for isometric maximal voluntary contraction (MVC) torque (18.9%) compared with fascicle force (14.6%; P = 0.025) and physiological cross‐sectional area (PCSA; 17.2%) compared with anatomical cross‐sectional area (ACSA, 13.0%; P < 0.0005). The relationship between ACSA and isometric MVC torque (r² = 0.56) was weaker than that between PCSA and fascicle force (r² = 0.68). Conclusions: These results provide a normative data set on inter‐individual variability in a variety of muscle strength‐related measurements and illustrate the benefit of using more stringent measures of muscle properties. Muscle Nerve 49 : 879–886, 2014     

Reliability of the log‐transformed EMG amplitude‐power output relationship for incremental knee‐extensor ergometry

Introduction: The purpose of this investigation was to determine the reproducibility of the log‐transformed model for electromyography (EMG) amplitude during incremental single‐leg knee‐extensor exercise. Methods: Eight healthy college‐aged men performed 3 incremental tests on separate occasions on a knee‐extensor ergometer. EMG amplitude was analyzed for each participant on each occasion for the rectus femoris and vastus medialis muscles at 4 different exercise power outputs (30%, 50%, 70%, and 90%) corresponding to each participant's maximal power output. Intraclass correlation coefficients (ICC) were determined for the slope and y‐intercept terms derived from the log‐transformed EMG amplitude‐power output relationship for each muscle. Results: The ICC values for the rectus femoris (slope = 0.779; y‐intercept = 0.787) and vastus medialis (slope = 0.756; y‐intercept = 0.763) muscles were high. Conclusions: The log‐transformed EMG amplitude‐power output relationship is a reliable index for measuring motor unit activation. Muscle Nerve 52:428–434, 2015     

Twitch and M‐wave potentiation induced by intermittent maximal voluntary quadriceps contractions: Differences between direct quadriceps and femoral nerve stimulation

Introduction: The aim of this study was to investigate differences in twitch and M‐wave potentiation in the quadriceps femoris when electrical stimulation is applied over the quadriceps muscle belly versus the femoral nerve trunk. Methods: M‐waves and mechanical twitches were evoked using direct quadriceps muscle and femoral nerve stimulation between 48 successive isometric maximal voluntary contractions (MVC) from 10 young, healthy subjects. Potentiation was investigated by analyzing the changes in M‐wave amplitude recorded from the vastus medialis (VM) and vastus lateralis (VL) muscles and in quadriceps peak twitch force. Results: Potentiation of twitch, VM M‐wave, and VL M‐wave were greater for femoral nerve than for direct quadriceps stimulation (P < 0.05). Despite a 50% decrease in MVC force, the amplitude of the M‐waves increased significantly during exercise. Conclusions: In addition to enhanced electrogenic Na⁺‐K⁺ pumping, other factors (such as synchronization in activation of muscle fibers and muscle architectural properties) may significantly influence the magnitude of M‐wave enlargement. Muscle Nerve 48 : 920–929, 2013     

Shifts in EMG spectral power during fatiguing dynamic contractions

Introduction: We examined the etiology of the electromyographic (EMG) spectral shift during dynamic fatigue. Methods: Nineteen subjects (mean ± SD age = 22.4 ± 1.6 years) performed 50 consecutive maximal concentric isokinetic contractions of dominant leg extensors. Surface EMG signals were detected from the vastus lateralis, rectus femoris, and vastus medialis during each contraction, processed with a wavelet analysis, and the resulting spectra were decomposed with a nonparametric spectral decomposition procedure. Results: The results indicated that the decreases in EMG frequency during the 50 contractions were generally due to reductions in high‐frequency power and increases in low‐frequency power. In addition, the spectral shifts were most pronounced for the rectus femoris, followed by the vastus lateralis, and then the vastus medialis. Conclusions: The spectral decomposition procedure is much more sensitive for tracking dynamic fatigue than is EMG mean frequency or median frequency. Muscle Nerve 50 : 95–102, 2014     

High resolution manometry patterns distinguish acid sensitivity in non-cardiac chest pain

Background High resolution manometry (HRM) has demonstrated two distinct smooth muscle contraction segments in the esophageal body; changes in these segments typify certain esophageal disorders. We investigated segmental characteristics in subgroups of non‐cardiac chest pain (NCCP). Methods 32 NCCP subjects were segregated into a GERD group (ambulatory pH testing off antisecretory therapy showing elevated total acid exposure time, AET ≥ 4.0% and positive symptom association probability, SAP) and an acid sensitive group (normal AET and positive SAP). HRM Clouse plots were analyzed; smooth muscle segment lengths, pressure amplitude peaks were measured for segment 2 and segment 3 (proximal and distal smooth muscle segments). Pressure volumes were determined in mmHg cm^?1 s^?1 for each peristaltic segment, and ratios of segment 3 : segment 2 calculated. Values were compared to a cohort of 14 normal controls. Key Results A distinctive shift in peak contraction amplitude to segment 3 was evident in the acid sensitive group (segment 2, 100.03 ± 11.06 mmHg, segment 3, 145.23 ± 10.29 mmHg, P = 0.006). Pressure volumes were similarly shifted to segment 3 (segment 2: 855.3 ± 135.1 mmHg cm^?1 s^?1, segment 3: 2115.2 ± 218.6 mmHg cm^?1 s^?1, P < 0.005). In contrast, peak amplitude and pressure volume were near equal in the two segments in GERD and control groups. A threshold segment 3 : segment 2 pressure volume ratio of 1.9 had the best performance characteristic for segregating acid sensitivity subjects from all GERD and control subjects. Conclusions & Inferences Shift in contractile vigor to the third peristaltic segment may be seen in acid sensitive subjects. HRM characteristics of smooth muscle contraction segments are of value in making this determination.     

Muscular adaptations and insulin‐like growth factor‐1 responses to resistance training are stretch‐mediated

Introduction: Modulation of muscle characteristics was attempted through altering muscle stretch during resistance training. We hypothesized that stretch would enhance muscle responses. Methods: Participants trained for 8 weeks, loading the quadriceps in a shortened (SL, 0–50° knee flexion; n = 10) or lengthened (LL, 40–90°; n = 11) position, followed by 4 weeks of detraining. Controls (CON; n = 10) were untrained. Quadriceps strength, vastus lateralis architecture, anatomical cross‐sectional area (aCSA), and serum insulin‐like growth factor‐1 (IGF‐1) were measured at weeks 0, 8, 10, and 12. Results: Increases in fascicle length (29 ± 4% vs. 14 ± 4%), distal aCSA (53 ± 12% vs. 18 ± 8%), strength (26 ± 6% vs. 7 ± 3%), and IGF‐1 (31 ± 6% vs. 7 ± 6%) were greater in LL compared with SL muscles (P < 0.05). No changes occurred in CON. Detraining decrements in strength and aCSA were greater in SL than LL muscles (P < 0.05). Conclusions: Enhanced muscle in vivo (and somewhat IGF‐1) adaptations to resistance training are concurrent with muscle stretch, which warrants its inclusion within training. Muscle Nerve 49 : 108–119, 2014     

Relative differences in strength and power from slow to fast isokinetic velocities may reflect dynapenia

Introduction: We compared absolute and normalized values for peak torque (PT), mean power (MP), rate of velocity development, and electromyography (EMG) amplitude during maximal isometric and concentric isokinetic leg extension muscle actions, as well as the %decrease in PT and %increase in MP from 1.05 to 3.14 rad·s^?1 in younger versus older men. Methods: Measurements were performed twice for reliability. Isokinetic measurements were normalized to the isometric muscle actions. Results: Absolute isometric PT, isokinetic PT and MP, and EMG amplitudes at 1.05 and 3.14 rad·s^?1 were greater in the younger men, although normalizing to isometric PT eliminated the age differences. The older men exhibited greater %decrease in PT (37.2% vs. 31.3%) and lower %increase in MP (87.6% vs. 126.4%) regardless of normalization. Conclusions: Normalization eliminated absolute differences in isokinetic strength and power, but the relative differences from slow to fast velocities may reflect dynapenia characterized by age‐related decreases in fast‐twitch fiber function. Muscle Nerve 52 : 120–130, 2015     

Effect of itopride on gastric emptying in longstanding diabetes mellitus

Abstract Delayed gastric emptying (GE) occurs in 30–50% of patients with longstanding type 1 or 2 diabetes, and represents a major cause of morbidity. Current therapeutic options are limited. We aimed at evaluating the effects of itopride on GE in patients with longstanding diabetes. Twenty‐five patients (20 type 1, 5 type 2; 10 males, 15 females; mean age 45.2 ± 2.7 years; body mass index 27.5 ± 0.9 kg m^?2; duration of diabetes 20.2 ± 2.4 years) were enrolled in a double‐blind, placebo‐controlled, randomized, crossover trial. Subjects received both itopride (200 mg) and placebo t.i.d. for 7 days, with a washout of 7–14 days. GE (scintigraphy), blood glucose (glucometer) and upper gastrointestinal (GI) symptoms (questionnaire) were measured following each treatment period. The test meal comprised 100 g ground beef (^99mTc‐sulphur colloid) and 150 mL of 10% dextrose [⁶⁷Ga‐ethylenediaminetetraacetic acid (EDTA)]. There was a slight trend for itopride to accelerate both solid (P = 0.09) and liquid (P = 0.09) GE. With itopride treatment, the emptying of both solids and liquids tended to be more accelerated, as the emptying with placebo was slower (solids: r = 0.39, P = 0.057; liquids: r = 0.44, P < 0.03). Twelve (48%) patients had delayed solid and/or liquid GE on placebo and in this group, itopride modestly accelerated liquid (P < 0.05), but not solid (P = 0.39), emptying. Itopride had no effect on mean blood glucose during the GE measurement (placebo: 9.8 ± 0.6 mmol L^?1vs itopride: 9.6 ±0.6 mmol L^?1), or GI symptoms (placebo: 1.4 ± 0.4 vs itopride: 1.8 ± 0.5). Itopride, in a dose of 200 mg t.i.d. for 7 days, tends to accelerate GE of liquids and solids in longstanding diabetes. The magnitude of this effect appears to be modest and possibly dependent on the rate of GE without itopride.     

25The effect of lipase supplementation on upper gastrointestinal symptoms and gastric myoelectrical activity induced by a high fat meal in healthy volunteers.

Background/Aims: Dyspepsia symptoms of abdominal discomfort, fullness, early satiety, and nausea occur after ingestion of meals in 20–30% of the population. Gastric dysrhythmias are exhibited by approximately 55% of dyspepsia patients. Currently there are limited therapies to reduce these symptoms. Gastric and pancreatic lipases are key enzymes in fat digestion, and hydrolyze fat into fatty acids and monoglycerides. The aims of this study were to characterize the effects of a high fat meal on upper gastrointestinal symptoms and gastric myoelectrical activity, and to evaluate the effect of acid‐resistant lipase supplementation on the same outcomes. Methods: Sixteen healthy volunteers enrolled in a double‐blind, placebo controlled, cross‐over trial were given a high fat meal (Pulmocare^®) that was 55% fat, 28% carbohydrates, and 17% protein (237 ml; 355 Kcal). A capsule containing 280 mg of acid‐resistant lipase (Amano Enzyme USA) or placebo was administered immediately before ingestion of the meal. The order of conditions was counterbalanced, and visits were separated by at least one week. At each visit, individuals completed a Visual Analog Scale (VAS) concerning symptoms of nausea, stomach fullness, hunger, bloating, and abdominal discomfort at baseline, immediately after the meal, and at 10, 20, 30, 45, and 60 minutes after the meal. Electrogastrograms (EGGs) were recorded throughout each visit to assess gastric myoelectrical activity. Results: Nausea, bloating, and stomach fullness were significantly increased 10 min after ingestion of the meal (ps < 0.05), and hunger was significantly decreased (p < 0.001); there was also a significant decrease in normal gastric myoelectrical activity (3 cycles min^?1), and a significant increase in tachygastria (3.7–10 cycles min^?1) at 10 min after the meal (ps < 0.05). By 45 min after the meal, dyspepsia symptoms and tachygastria had decreased significantly from immediately after the meal, and normal gastric myoelectrical activity had increased significantly (ps < 0.05). Stomach fullness was significantly lower with lipase supplementation than with placebo condition at 20 and 30 min after the meal (p < 0.05); no effect of lipase supplementation on gastric myoelectrical activity was detected. Conclusions: (1) The high fat meal induced dyspepsia symptoms and gastric dysrhythmias, suggesting the meal may be a useful test for assessing gastric neuromuscular disorders; and (2) Acid‐resistant lipase supplementation decreased stomach fullness after ingestion of the meal, and warrants further study in individuals with functional dyspepsia.     

Prior heat stress effects fatigue recovery of the elbow flexor muscles

Introduction: Long‐lasting alterations in hormones, neurotransmitters, and stress proteins after hyperthermia may be responsible for the impairment in motor performance during muscle fatigue. Methods: Subjects (n = 25) performed a maximal intermittent fatigue task of elbow flexion after sitting in either 73° or 26°C to examine the effects of prior heat stress on fatigue mechanisms. Results: The heat stress increased the tympanic and rectal temperatures by 2.3° and 0.82°C, respectively, but there was full recovery prior to the fatigue task. Although prior heat stress had no effects on fatigue‐related changes in volitional torque, electromyographic (EMG) activity, torque relaxation rate, motor evoked potential (MEP) size, and silent period (SP) duration, prior heat stress acutely increased the pre‐fatigue relaxation rate and chronically prevented long‐duration fatigue (P < 0.05). Conclusions: These findings indicate that prior passive heat stress alone does not alter voluntary activation during fatigue, but prior heat stress and exercise produce longer‐term protection against long‐duration fatigue. Muscle Nerve 44: 115–125, 2011     

The nitric oxide synthase inhibitor, Ng-nitro-l-arginine-methyl-ester, attenuates the delay in gastric emptying induced by hyperglycaemia in healthy humans

Abstract The aim of this study was to determine whether the nitric oxide (NO) synthase inhibitor, N^g‐nitro‐l ‐arginine‐methyl‐ester (l ‐NAME), reverses the effects of acute hyperglycaemia on gastric emptying and antropyloroduodenal (APD) motility. The study had a four‐way randomized crossover (hyperglycaemia vs euglycaemia; l ‐NAME vs placebo) design in a clinical laboratory setting. Seven healthy volunteers [four males; age 30.3 ± 3.8 years; body mass index (BMI) 23.6 ± 1.2 kg m^?2] were the study subjects. After positioning a transnasal manometry catheter across the pylorus, the blood glucose concentration was maintained at either 15 or 5 mmol L^?1 using a glucose/insulin clamp. An intravenous infusion of l ‐NAME (180 μg kg^?1 h^?1) or placebo (0.9% saline) was commenced (T = ?30 min) and continued for 150 min. At T = ?2 min, subjects ingested a drink containing 50 g of glucose made up to 300 mL with water. Gastric emptying was measured using 3D ultrasound, and APD motility using manometry. Hyperglycaemia slowed gastric emptying (P < 0.05), and this effect was abolished by l ‐NAME. l ‐NAME had no effect on gastric emptying during euglycaemia. Hyperglycaemia suppressed fasting antral motility [motility index: 3.9 ± 0.8 (hyperglycaemia) vs 6.5 ± 0.6 (euglycaemia); P < 0.01]; l ‐NAME suppressed postprandial antral motility [motility index: 3.6 ± 0.2 (l ‐NAME) vs 5.1 ± 0.2 (placebo); P < 0.001]. Postprandial basal pyloric pressure was higher during hyperglycaemia (P < 0.001), and lower after administration of l ‐NAME (P < 0.001). Slowing of gastric emptying induced by hyperglycaemia is mediated by NO, and may involve the modulation of tonic pyloric activity.     

Vastus lateralis NA+‐K+‐ATpase activity,protein, and isoform distribution in chronic obstructive pulmonary disease

In this study we investigate the hypothesis that protein abundance, isoform distribution, and maximal catalytic activity of sodium–potassium–adenosine triphosphatase (Na⁺‐K⁺‐ATPase) would be altered in muscle of patients with moderate to severe chronic obstructive pulmonary disease (COPD). Tissue samples were obtained from the vastus lateralis of 10 patients with COPD (mean ± SE: age = 67 ± 2.9 years; FEV₁ = 39 ± 5.5%) and 10 healthy, matched controls (CON: age = 68 ± 2 years; FEV₁ = 114 ± 4.2%). The samples were assessed for maximal catalytic activity (V_max) of the enzyme using the K⁺‐stimulated 3‐O‐methylfluorescein‐phosphatase (3‐O‐MFPase) assay, enzyme abundance using the [³H]‐ouabain assay, and isoform content of both α (α₁, α₂, α₃) and β (β₁, β₂, β₃) using Western blot techniques. A 19.4% lower (P < 0.05) V_max was observed in COPD compared with CON (90.7 ± 6.7 vs. 73.1 ± 4.7 nmol · mg protein^?1 h^?1). No differences between groups were observed for pump concentration (259 ± 15 vs. 243 ± 17 pmol · g wet weight). For the isoforms, α₁ was decreased by 28% (P < 0.05), and α₂ was increased by 12% (P < 0.05) in COPD compared with CON. No differences between groups were observed for α₃ or for the β isoforms. We conclude that moderate COPD compromises V_max, which occurs in the absence of changes in pump abundance. The reduction in V_max could be due to a shift in isoform expression (α₁, α₂), alterations in intrinsic regulation, or to structural changes in the enzyme. The changes observed in the catalytic activity of the pump could have major effects on membrane excitability and fatigability, which are typically compromised in COPD. Muscle Nerve, 2009     

Afferent nerve sensitivity is decreased by an iNOS-dependent mechanism during indomethacin-induced inflammation in the murine jejunum in vitro

Abstract Evidence exists that visceral afferent sensitivity is subject to regulatory mechanisms. We hypothesized that afferent sensitivity is decreased in the small intestine during intestinal inflammation by an inducible nitric oxide synthase (iNOS)‐dependent mechanism. C57BL/6 mice were injected twice with vehicle or 60 mg kg^?1 indomethacin subcutaneously to induce intestinal inflammation. Afferent sensitivity was recorded on day 3 from a 2‐cm segment of jejunum in vitro by extracellular multi‐unit afferent recordings from the mesenteric nerve bundle. In subgroups (n = 6), iNOS was inhibited selectively by L‐N6‐(1‐iminoethyl)‐lysine (L‐NIL) given either chronically from day 1–3 (3 mg kg^?1 twice daily i.p.) or acutely into the organ bath (30 μmol L^?1). The indomethacin‐induced increase of macroscopic and microscopic scores of intestinal inflammation (both P < 0.05) were unchanged after pretreatment with L‐NIL. Peak afferent firing following bradykinin (0.5 μmol L^?1) was 55 ± 8 impulse s^?1 during inflammation vs 97 ± 7 impulse s^?1 in controls (P < 0.05). Normal firing rate was preserved following L‐NIL pretreatment (112 ± 16 impulse s^?1) or acute administration of L‐NIL (108 ± 14 impulse s^?1). A similar L‐NIL dependent reduction was observed for 5‐HT (250 μmol L^?1) and mechanical ramp distension from 20 to 60 cmH₂O (both P < 0.05). Intraluminal pressure peaks were decreased to 0.66 ± 0.1 cmH₂O during inflammation compared to 2.51 ± 0.3 in controls (P < 0.01). Afferent sensitivity is decreased by an iNOS‐dependent mechanism during intestinal inflammation which appears to be independent of the inflammatory response. This suggests that iNOS‐dependent nitric oxide production alters afferent sensitivity during inflammation by interfering with signal transduction to afferent nerves rather than by attenuating intestinal inflammation.     

Safety and efficacy of ghrelin agonist TZP‐101 in relieving symptoms in patients with diabetic gastroparesis: a randomized,placebo‐controlled study

Background Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP‐101, is in clinical development for treatment of gastroparesis. This double‐blind, randomized, placebo‐controlled study evaluated the safety and efficacy of multiple TZP‐101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. Methods Patients were admitted to the hospital and adaptively randomized to receive a single 30‐min intravenous infusion of 20, 40, 80, 160, 320, or 600 μg kg^?1 TZP‐101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient‐rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. Key Results The 80 μg kg^?1 dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 μg kg^?1 dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal‐related GSA scores for Postprandial fullness were significantly improved in the 80 μg kg^?1 TZP‐101 group compared with placebo (P = 0.012). Clinicians rated the 80 μg kg^?1 group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP‐101 groups and all doses were well‐tolerated. Conclusions & Inferences TZP‐101 appears to be safe, well‐tolerated, and effective at acutely addressing several gastroparesis symptoms.