Gender-specific vascular effects elicited by chronic ethanol consumption in rats: a role for inducible nitric oxide synthase

Background and purpose: Epidemiological data suggest that the risk of ethanol-associated cardiovascular disease is greater in men than in women. This study investigates the mechanisms underlying gender-specific vascular effects elicited by chronic ethanol consumption in rats. Experimental approach: Vascular reactivity experiments using standard muscle bath procedures were performed on isolated thoracic aortae from rats. mRNA and protein for inducible NO synthase (iNOS) and for endothelial NOS (eNOS) was assessed by RT-PCR or western blotting, respectively. Key results: In male rats, chronic ethanol consumption enhanced phenylephrine-induced contraction in both endothelium-intact and denuded aortic rings. However, in female rats, chronic ethanol consumption enhanced phenylephrine-induced contraction only in endothelium denuded aortic rings. After pre-incubation of endothelium-intact rings with L-NAME, both male and female ethanol-treated rats showed larger phenylephrine-induced contractions in aortic rings, compared to the control group. Acetylcholine-induced relaxation was not affected by ethanol consumption. The effects of ethanol on responses to phenylephrine were similar in ovariectomized (OVX) and intact (non-OVX) female rats. In the presence of aminoguanidine, but not 7-nitroindazole, the contractions to phenylephrine in rings from ethanol-treated female rats were greater than that found in control tissues in the presence of the inhibitors. mRNA levels for eNOS and iNOS were not altered by ethanol consumption. Ethanol intake reduced eNOS protein levels and increased iNOS protein levels in aorta from female rats. Conclusions and implications: Gender differences in the vascular effects elicited by chronic ethanol consumption were not related to ovarian hormones but seemed to involve the upregulation of iNOS.

Detrusor overactivity is associated with downregulation of large-conductance calcium- and voltage-activated potassium channel protein

Chang S, Gomes CM, Hypolite JA, Marx J, Alanzi J, Zderic SA, Malkowicz B, Wein AJ, Chacko S. Detrusor overactivity is associated with downregulation of large-conductance calcium-and voltage-activated potassium channel protein. Am J Physiol Renal Physiol 298: F1416-F1423, 2010. First published April 14, 2010; doi: 10.1152/ajprenal.00595.2009.-Large-conductance voltage-and calcium-activated potassium (BK) channels have been shown to play a role in detrusor overactivity (DO). The goal of this study was to determine whether bladder outlet obstructioninduced DO is associated with downregulation of BK channels and whether BK channels affect myosin light chain 20 (MLC(20)) phosphorylation in detrusor smooth muscle (DSM). Partial bladder outlet obstruction (PBOO) was surgically induced in male New Zealand White rabbits. The rabbit PBOO model shows decreased voided volumes and increased voiding frequency. DSM from PBOO rabbits also show enhanced spontaneous contractions compared with control. Both BK channel alpha- and beta-subunits were significantly decreased in DSM from PBOO rabbits. Immunostaining shows BK beta mainly expressed in DSM, and its expression is much less in PBOO DSM compared with control DSM. Furthermore, a translational study was performed to see whether the finding discovered in the animal model can be translated to human patients. The urodynamic study demonstrates several overactive DSM contractions during the urine-filling stage in benign prostatic hyperplasia (BPH) patients with DO, while DSM is very quiet in BPH patients without DO. DSM biopsies revealed significantly less BK channel expression at both mRNA and protein levels. The degree of downregulation of the BK beta-subunit was greater than that of the BK alpha-subunit, and the downregulation of BK was only associated with DO, not BPH. Finally, the small interference (si) RNA-mediated downregulation of the BK beta-subunit was employed to study the effect of BK depletion on MLC(20) phosphorylation. siRNA-mediated BK channel reduction was associated with an increased MLC(20) phosphorylation level in cultured DSM cells. In summary, PBOO-induced DO is associated with downregulation of BK channel expression in the rabbit model, and this finding can be translated to human BPH patients with DO. Furthermore, downregulation of the BK channel may contribute to DO by increasing the basal level of MLC(20) phosphorylation.

Implications of prevalent and incident diabetes mellitus on left ventricular geometry and function in the ageing heart: The MONICA/KORA Augsburg cohort study

Background and Aim: It is unclear to what extent diabetes modulates the ageing-related adaptations of cardiac geometry and function. Methods and Results: We examined 1005 adults, aged 25-74 years, from a population-based survey at baseline in 1994/5 and at follow-up in 2004/5. We compared persistently non-diabetic individuals (ND; no diabetes at baseline and at follow-up, n = 833) with incident (ID; non-diabetic at baseline and diabetic at follow-up, n = 36) and with prevalent diabetics (PD; diabetes at baseline and follow-up examination, n = 21). Left ventricular (LV) geometry and function were evaluated by echocardiography. Statistical analyses were performed with multivariate linear regression models. Over ten years the PD group displayed a significantly stronger relative increase of LV mass (+9.34% vs. +23.7%) that was mediated by a more pronounced increase of LV end-diastolic diameter (+0% vs. +6.95%) compared to the ND group. In parallel, LA diameter increased (+4.50% vs. +12.7%), whereas ejection fraction decreased (+3.02% vs. -4.92%) more significantly in the PD group. Moreover, at the follow-up examination the PD and ID groups showed a significantly worse diastolic function, indicated by a higher E/EM ratio compared with the ND group (11.6 and 11.8 vs. 9.79, respectively). Conclusions: Long-standing diabetes was associated with an acceleration of age-related changes of left ventricular geometry accumulating in an eccentric remodelling of the left ventricle. Likewise, echocardiographic measures of systolic and diastolic ventricular function deteriorated more rapidly in individuals with diabetes. (C) 2009 Elsevier B.V. All rights reserved.

Elevation of Uterine Basal Tone and Fetal Heart Rate Abnormalities After Labor Analgesia A Randomized Controlled Trial

OBJECTIVE: To estimate the effects of combined spinal-epidural and traditional epidural analgesia on uterine basal tone and its association with the occurrence of fetal heart rate (FHR) abnormalities. METHODS: Seventy-seven laboring patients who requested pain relief during labor were randomly assigned to combined spinal-epidural (n=41) or epidural analgesia (n=36). Uterine contractions and FHR were recorded 15 minutes before and after analgesia. Uterine tone was evaluated with intrauterine pressure catheter. Primary outcomes were the elevation of baseline uterine tone and occurrence of FHR prolonged decelerations or bradycardia after analgesia. The influence of other variables such as oxytocin use, hypotension, and speed of pain relief were estimated using a logistic regression model. RESULTS: The incidence of all outcomes was significantly greater in the combined spinal-epidural group compared with epidural: uterine hypertonus (17 compared with 6; P=.018), FHR abnormalities (13 compared with 2; P<.01), and both events simultaneously (11 compared with 1; P<.01). Logistic regression analysis showed the type of analgesia as the only independent predictor of uterine hypertonus (odds ratio 3.526, 95% confidence interval 1.21-10.36; P=.022). For the occurrence of FHR abnormalities, elevation of uterine tone was the independent predictor (odds ratio 18.624, 95% confidence interval 4.46-77.72; P<.001). Regression analysis also found a correlation between decrease on pain scores immediately after analgesia and the estimated probability of occurrence of hypertonus and FHR abnormalities. CONCLUSION: Combined spinal-epidural analgesia is associated with a significantly greater incidence of FHR abnormalities related to uterine hypertonus compared with epidural analgesia. The faster the pain relief after analgesia, the higher the probability of uterine hypertonus and FHR changes. CLINICAL TRIAL REGISTRATION: Umin Clinical Trials Registry, http://www.umin.ac.jp/ctr/index.htm, UMIN000001186

Reliability of electromyographic amplitude values of the upper limb muscles during closed kinetic chain exercises with stable and unstable surfaces

The purpose of the present study was to evaluate the intra and interday reliability of surface electromyographic amplitude values of the scapular girdle muscles and upper limbs during 3 isometric closed kinetic chain exercises, involving upper limbs with the fixed distal segment extremity on stable base of support and on a Swiss ball (relatively unstable). Twenty healthy adults performed the exercises push-up, bench-press and wall-press with different effort levels (80% and 100% maximal load). Subjects performed three maximal voluntary contractions (MVC) in muscular testing position of each muscle to obtain a reference value for root mean square (RMS) normalization. Individuals were instructed to randomly perform three isometric contraction series, in which each exercise lasted 6 s with a 2-min resting-period between series and exercises. Intra and interday reliabilities were calculated through the intraclass correlation coefficient (ICC 2.1), standard error of the measurement (SEM). Results indicated an excellent intraday reliability of electromyographic amplitude values (ICC >= 0.75). The interday reliability of normalized RMS values ranged between good and excellent (ICC 0.52-0.98). Finally, it is suggested that the reliability of normalized electromyographic amplitude values of the analyzed muscles present better values during exercises on a stable surface. However, load levels used during the exercises do not seem to have any influence on variability levels, possibly because the loads were quite similar. (C) 2007 Elsevier Ltd. All rights reserved.

Activation of the shoulder and arm muscles during axial load exercises on a stable base of support and on a medicine ball

The purpose of this study was to compare SEMG activities during axial load exercises on a stable base of support and on a medicine ball (relatively unstable). Twelve healthy male volunteers were tested (x = 23 +/- 7y). Surface EMG was recorded from the biceps brachii, anterior deltoid, clavicular portion of pectoralis major, upper trapezius and serratus anterior using surface differential electrodes. All SEMG data are reported as percentage of RMS mean values obtained in maximal voluntary contractions for each muscle studied. A 3-way within factor repeated measures analysis of variance was performed to compare RMS normalized values. The RMS normalized values of the deltoid were always greater during the exercises performed on a medicine ball in relation to those performed on a stable base of support. The trapezius showed greater mean electric activation amplitude values on the wall-press exercise on a medicine ball, and the pectoralis major on the push-up. The serratus and biceps did not show significant differences of electric activation amplitude in relation to both tested bases of support. Independent of the base of support, none of the studied muscles showed significant differences of electric activation amplitude during the bench-press exercise. The results contribute to the identification of the levels of muscular activation amplitude during exercises that are common in clinical practice of rehabilitation of the shoulder and the differences in terms of type of base of support used. (C) 2006 Elsevier Ltd. All rights reserved.

ELECTROMYOGRAPHIC AMPLITUDE RATIO OF SERRATUS ANTERIOR AND UPPER TRAPEZIUS MUSCLES DURING MODIFIED PUSH-UPS AND BENCH PRESS EXERCISES

Imbalance and weakness of the serratus anterior and upper trapezius force couple have been described in patients with shoulder dysfunction. There is interest in identifying exercises that selectively activate these muscles and including it in rehabilitation protocols. This study aims to verify the UT/SA electromyographic (EMG) amplitude ratio, performed in different upper limb exercises and on two bases of support. Twelve healthy men were tested (average age = 22.8 +/- 3.1 years), and surface EMG was recorded from the upper trapezius and serratus anterior using single differential surface electrodes. Volunteers performed isometric contractions over a stable base of support and on a Swiss ball during the wall push-up (WP), bench press (BP), and push-up (PU) exercises. All SEMG data are reported as a percentage of root mean square or integral of linear envelope from the maximal value obtained in one of three maximal voluntary contractions for each muscle studied. A linear mixed-effect model was performed to compare UT/SA ratio values. The WP, BP, and PU exercises showed UT/SA ratio mean +/- SD values of 0.69 +/- 0.72, 0.14 +/- 0.12, and 0.39 +/- 0.37 for stable surfaces, respectively, whereas for unstable surfaces, the values were 0.73 +/- 0.67, 0.43 +/- 0.39, and 0.32 +/- 0.30. The results demonstrate that UT/SA ratio was influenced by the exercises and by the upper limb base of support. The practical application is to show that BP on a stable surface is the exercise preferred over WP and PU on either surfaces for serratus anterior muscle training in patients with imbalance between the UT/SA force couple or serratus anterior weakness.

Electromyographic Analysis of Paravertebral Muscles in Patients with Idiopathic Scoliosis

Study Design. Prospective clinical electromyographic study in adolescents with idiopathic scoliosis and control group. Objective. To evaluate electromyographic amplitude from erector spinae muscles of patients with idiopathic scoliosis in comparison with control volunteers without spinal deformities. Summary of Background Data. Previous studies have indicated an increased electromyographic activity in paravertebral muscles in the convex side of the scoliotic curvature. However, in previous studies there is the absence or poor description of methods used, and some studies were conducted before the recording and processing recommendations for surface electromyographic signals had been described. Methods. Thirty individuals, matched by sex, age, and body mass index, were divided into two groups: scoliosis and control. The electric activity of the erector spinae muscles was determined by surface electromyography on both sides of the three levels of spine: T8, L2, and L5. Results. Normalized electromyographic amplitudes of erector spinae muscles, in the convex and concave sides of the apex region of the scoliotic curve in the thoracic and lumbar regions, were not significantly different. Also, there was no significant difference between the muscles of these regions when the scoliosis group was compared with the control group. The erector spinae muscle at the L5 level, representing the lower vertebral limit of the lumbar scoliotic curve, had significantly higher electromyographic activity on the convex side. However, the same alteration was shown in the control group homologous muscle (on the left side). Conclusion. Erector spinae muscles on the convex and concave sides at the curvature apex in patients with idiopathic scoliosis and small magnitude of curves did not show significant differences in electromyographic amplitude. Future studies should evaluate whether intragroup activation differences, at the L5 level in 80% of the maximum voluntary isometric contractions with predominance of the left side of the vertebral column, have any relation to the condition.

Gastrointestinal dysmotility in 5-fluorouracil-induced intestinal mucositis outlasts inflammatory process resolution

Aim To evaluate gastrointestinal motility during 5-fluorouracil (5-FU)-induced intestinal mucositis. Materials and methods Wistar rats received 5-FU (150 mg kg(-1), i.p.) or saline. After the 1st, 3rd, 5th, 15th and 30th day, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage, apoptotic and mitotic indexes, MPO activity and GSH concentration. In order to study gastrointestinal motility, on the 3rd or 15th day after 5-FU treatment, gastric emptying in vivo was measured by scintilographic method, and stomach or duodenal smooth muscle contractions induced by CCh were evaluated in vitro. Results On the third day of treatment, 5-FU induced a significant villi shortening, an increase in crypt depth and intestinal MPO activity and a decrease in villus/crypt ratio and GSH concentration. On the first day after 5-FU there was an increase in the apoptosis index and a decrease in the mitosis index in all intestinal segments. After the 15th day of 5-FU treatment, a complete reversion of all these parameters was observed. There was a delay in gastric emptying in vivo and a significant increase in gastric fundus and duodenum smooth muscle contraction, after both the 3rd and 15th day. Conclusions 5-FU-induced gastrointestinal dysmotility outlasts intestinal mucositis.

Ethanol consumption increases blood pressure and alters the responsiveness of the mesenteric vasculature in rats

Chronic ethanol Consumption and hypertension are related. In the current study we investigated whether changes in reactivity of the mesenteric arterial bed could account for the increased blood pressure associated with chronic ethanol intake. Changes in reactivity to phenylephrine and acetylcholine were investigated in the perfused mesenteric bed from rats treated with ethanol for 2 or 6 weeks and their age-matched controls. Mild hypertension was observed in chronically ethanol-treated rats. Treatment of rats for 6 weeks induced an increase in the contractile response of endothelium-intact mesenteric bed to phenylephrine, but not denuded rat mesenteric bed. The phenylephrine-induced increase in perfusion pressure was not altered after 2 weeks` treatment with ethanol. Moreover, acetylcholine-induced endothelium-dependent relaxation was reduced by ethanol treatment for 6 weeks, but not 2 weeks. Pre-treatment with indometacin, a cyclooxygenase inhibitor, reduced the maximum effect induced by phenylephrine (E-max) in endothelium-intact mesenteric bed from both control and ethanol-treated rats. No differences in the E-max values for phenylephrine were observed between groups in the presence of indometacin. L-NNA, a nitric oxide (NO) synthase (NOS) inhibitor, increased the E-max for phenylephrine in endothelium-intact mesenteric bed from control rats but not from ethanol-treated rats. Levels of endothelial NOS (eNOS) mRNA were not altered by chronic ethanol consumption. However, chronic ethanol intake strongly reduced eNOS protein levels in the mesenteric bed. This study shows that chronic ethanol consumption increases blood pressure and alters the reactivity of the mesenteric bed. Moreover, the increased vascular response to phenylephrine observed in the mesenteric bed is maintained by two mechanisms: an increased release of endothelial-derived vasoconstrictor prostanoids and a reduced modulatory action of endothelial NO, which seems to be associated with reduced post-transcriptional expression of eNOS.

Oral and pharyngeal transit of a paste bolus in Chagas` disease

We measured the oral and pharyngeal transit of a paste bolus in 20 patients with Chagas` disease and 21 controls. Each subject swallowed of a 10-ml paste bolus prepared with 50 ml of water and 4.5 g of instant food thickener labeled with 55.5 MBq of 99(m) technetium phytate. After the scintigraphic recording of the transit, we delineated regions of interest (ROI) corresponding to mouth, pharynx, and proximal esophagus. Time-activity curves were generated for each ROI. There was no difference between patients with Chagas` disease and controls with respect to the duration of oral and pharyngeal transit, amount of pharyngeal residue, or flux of bolus entry into the proximal esophagus. The amount of oral residue was higher in patients with Chagas` disease (median = 0.71 ml) than in controls (median = 0.45 ml). The pharyngeal clearance duration was longer in patients with Chagas` disease (median = 0.85 s) than in controls (median = 0.60 s). The oral transit duration of the patients with Chagas` disease and dysphagia (median = 0.55 s, n = 14) was shorter than the oral transit duration of chagasic patients without dysphagia (median = 0.80 s, n = 6). We conclude that when swallowing a paste bolus, patients with Chagas` disease may have an increased amount of oral residue and a longer pharyngeal clearance duration than asymptomatic volunteers.

Muscle mass gain observed in patients with short bowel syndrome subjected to resistance training

Few studies are available about the evaluation of resistance training in patients with protein-energy malnutrition. To assess the effects of resistance training on the recovery of nutritional status of patients with short bowel syndrome, with a small bowel remnant of less than 100 cm, 9 patients of both sexes with protein-energy malnutrition after extensive resection of the small bowel were submitted to resistance training of progressive intensity consisting of concentric and eccentric work exercises for the upper limbs, trunk, and lower limbs, with the individuality and limitations of each patients being respected. Food consumption was monitored by 24-hour food recall performed during the initial phase of the study, before and 7 and 14 weeks after physical training, and by a dietary record for a period of 3 days of oral feeding. The nutrients administered by the enteral and parenteral route were recorded. A significant increase in total arm area (P <= .01) and fat-free mass (P <= .01) was observed as determined by computed tomography. An increase in total energy ingestion and carbohydrate consumption (P <= .01) was also observed. In addition, the activity of the enzyme carnosinase was increased after resistance training (P <= .01). The present results show that resistance training in patients with short bowel syndrome and protein-energy malnutrition can be considered to be a part of the nonmedicamentous treatment of these patients, leading to better nutrient use and to a gain of lean mass. (c) 2008 Elsevier Inc. All rights reserved.

Sildenafil inhibits duodenal contractility via activation of the NO-K+ channel pathway

Phosphodiesterase type-5 (PDE5) specifically cleaves cyclic guanosine monophosphate (cGMP), a key intracellular secondary messenger. The PDE5 inhibitor sildenafil is a well-known vasodilator that also has gastrointestinal myorelaxant properties. In the present study, we further investigated sildenafil-induced myorelaxation in rat isolated duodenum, assessing its interaction with nitric oxide (NO) synthase and K+ channel opening. The spontaneous contractions of duodenal strips were reversibly inhibited by sildenafil (0.1-300 mu M) in a concentration-dependent manner [mean (95% confidence interval); EC50 = 6.8 (2.7-17.3) mu M]. The sildenafil-induced myorelaxation was significantly decreased by the NO synthase inhibitor N-nitro-L-arginine methyl ester [increasing the EC50 value to 41.9 (26.1-67.3) mu M]. Sodium nitroprusside or forskolin pretreatments enhanced the sildenafil-induced myorelaxation. In isolated strips pretreated with BaCl2 (0.2 mM), 4-aminopyridine (4-AP, 3 mM), or glybenclamide (1 mu M), the sildenafil-induced EC50 value was significantly increased to 32.8 (19.1-56.4), 27.1 (15.2-48.3) and 20.1 (16.4-24.7) mu M, respectively. Minoxidil (50 mu M) or diazoxide (100 mu M) also significantly attenuated the sildenafil-induced potency. In conclusion, the NO synthase/cyclic nucleotide pathway activation is involved in sildenafil-induced inhibition of spontaneous duodenal contractions. Its pharmacological action seems to be influenced by K+ channel opening, especially the voltage-sensitive ones, being inhibited by 4-AP and K-ATP channels, sensitive to glybenclamide.

Perception of dysphagia: lack of correlation with objective measurements of esophageal function

Background The mechanism underlying increased perception of food bolus passage in the absence of esophageal mechanical obstruction has not been completely elucidated. A correlation between the intensity of the symptom and the severity of esophageal dysfunction, either motility (manometry) or bolus transit (impedance) has not been clearly demonstrated. The aim of this study was to analyze the correlation between objective esophageal function assessment (with manometry and impedance) and perception of bolus passage in healthy volunteers (HV) with normal and pharmacologically-induced esophageal hypocontractility, and in patients with gastro-esophageal reflux disease (GERD) with and without ineffective esophageal motility (IEM). Methods Combined manometry-impedance was performed in 10 HV, 19 GERD patients without IEM and nine patients with IEM. Additionally, nine HV were studied after 50 mg sildenafil, which induced esophageal peristaltic failure. Perception of each 5 mL viscous swallow was evaluated using a 5-point scale. Manometry identified hypocontractility (contractions lower than 30 mmHg) and impedance identified incomplete bolus clearance. Key Results In HV and in GERD patients with and without IEM, there was no association between either manometry or impedance and perception on per swallow analysis (OR: 0.842 and OR: 2.017, respectively), as well as on per subject analysis (P = 0.44 and P = 0.16, respectively). Lack of correlation was also found in HV with esophageal hypocontractility induced by sildenafil. Conclusions & Inferences There is no agreement between objective measurements of esophageal function and subjective perception of bolus passage. These results suggest that increased bolus passage perception in patients without mechanical obstruction might be due to esophageal hypersensitivity.

Validation of ACB in vitro and in vivo as a biomagnetic method for measuring stomach contraction

Background The aim of this study was to validate a biomagnetic method (alternate current biosusceptometry, ACB) for monitoring gastric wall contractions in rats. Methods In vitro data were obtained to establish the relationship between ACB and the strain-gauge (SG) signal amplitude. In vivo experiments were performed in pentobarbital-anesthetized rats with SG and magnetic markers previously implanted under the gastric serosa or after ingestion of magnetic material. Gastric motility was quantified from the tracing amplitudes and frequency profiles obtained by Fast Fourier Transform. Key Results The correlation between in vitro signal amplitudes was strong (R = 0.989). The temporal cross-correlation coefficient between the ACB and SG signal amplitude was higher (P < 0.0001) in the postprandial (88.3 +/- 9.1 V) than in the fasting state (31.0 +/- 16.9 V). Irregular signal profiles, low contraction amplitudes, and smaller signal-to-noise ratios explained the poor correlation between techniques for fasting-state recordings. When a magnetic material was ingested, there was also strong correlation in the frequency and signal amplitude and a small phase-difference between the techniques. The contraction frequencies using ACB were 0.068 +/- 0.007 Hz (postprandial) and 0.058 +/- 0.007 Hz (fasting) (P < 0.002) and those using SG were 0.066 +/- 0.006 Hz (postprandial) and 0.059 +/- 0.008 Hz (fasting) (P < 0.005). Conclusions & Inferences In summary, ACB is reliable for monitoring gastric wall contractions using both implanted and ingested magnetic materials, and may serve as an accurate and sensitive technique for gastrointestinal motility studies.