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ABSTRACT: Ca(2+) waves are initiated not only by Ca(2+) leak from the sarcoplasmic reticulum (SR), but also by Ca(2+) dissociation from the myofilaments in the myocardium with nonuniform contraction. We investigated whether contractile properties and the production of reactive oxygen species (ROS) affect Ca(2+) wave propagation. Trabeculae were obtained from 76 rat hearts. Force was measured with a strain gauge, sarcomere length with a laser diffraction technique, and [Ca(2+)](i) with fura-2 and a CCD camera (24°C, 2.0mmol/L [Ca(2+)](o)). ROS production was estimated from 2',7'-dichlorofluorescein (DCF) fluorescence. Trabeculae were regionally exposed to a jet of solution containing 1) 10mmol/L Ca(2+) to initiate Ca(2+) waves by SR Ca(2+) leak due to Ca(2+) overload within the jet-exposed region, and 2) 0.2mmol/L Ca(2+) or 5mmol/L caffeine to initiate such waves by Ca(2+) dissociation from the myofilaments due to nonuniform contraction. Ca(2+) waves were induced by stimulus trains for 7.5s. Ten-percent muscle stretch increased DCF fluorescence and accelerated Ca(2+) waves initiated due to both Ca(2+) overload and nonuniform contraction. Preincubation with 3 μmol/L diphenyleneiodonium or 10 μmol/L colchicine suppressed the increase in DCF fluorescence but suppressed acceleration of Ca(2+) waves initiated only due to Ca(2+) overload. Irrespective of preincubation with colchicine, reduction of force after the addition of 10 μmol/L blebbistatin did not decelerate Ca(2+) waves initiated due to Ca(2+) overload, while it did decelerate waves initiated due to nonuniform contraction. These results suggest that Ca(2+) wave propagation is modulated by ROS production through an intact microtubule network only during stretch and may be additionally modulated by Ca(2+) dissociated from the myofilaments in the case of nonuniform contraction.
Journal of Molecular and Cellular Cardiology 12/2012; · 5.17 Impact Factor
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ABSTRACT: Although budesonide/formoterol (BUD/FORM) is used clinically as a steroid/β(2)-agonist single inhaler, it has not yet been clarified whether BUD/FORM has inotropic effects on diaphragm muscles after inhalation.
We examined the effects of BUD/FORM inhalation, endotoxin injection, and BUD/FORM inhalation plus endotoxin injection on diaphragm contractile properties and nitric oxide (NO) production. After these three treatments, the diaphragm muscle was dissected, and its contractile properties were measured. Histochemistry for the reduced form of nicotinamide adenine dinucleotide phosphate diaphorase was performed for each muscle to assess NO production.
The force-frequency curves showed an upward shift 1 h after inhalation (p < 0.05) in the BUD/FORM inhalation only group. The force-frequency curves showed a downward shift 4 h after injection (p < 0.001) in the endotoxin injection groups. In the BUD/FORM inhalation plus endotoxin injection groups, a downward shift in the force-frequency curves at 4 h after endotoxin injection was prevented. NO production was inhibited in the BUD/FORM inhalation plus endotoxin injection group compared with that of the endotoxin injection only groups.
BUD/FORM inhalation has an inotropic effect on diaphragm muscle, protects diaphragm muscle deterioration after endotoxin injection, and inhibits NO production. Increments in muscle contractility with BUD/FORM inhalation are induced through a synergistic effect of an anti-inflammatory agent and β(2)-agonist.
Allergology International 07/2012; 61(3):439-49.
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ABSTRACT: In the ischemic myocardium, extracellular potassium ([K(+)](o)) increases to ≥20 mmol/l. To determine how lethal arrhythmias occur during ischemia, we investigated whether the increased spatial pattern of [K(+)](o), i.e., a regional or a global increase, affects the incidence of arrhythmias. Force, sarcomere length, membrane potential, and nonuniform intracellular Ca(2+) ([Ca(2+)](i)) were measured in rat ventricular trabeculae. A "regional" or "global" increase in [K(+)](o) was produced by exposing a restricted region of muscle to a jet of 30 mmol/l KCl or by superfusing trabeculae with a solution containing 30 mmol/l KCl, respectively. The increase in [Ca(2+)](i) (Ca(CW)) during Ca(2+) waves was measured (24°C, 3.0 mmol/l [Ca(2+)](o)). A regional increase in [K(+)](o) caused nonuniform [Ca(2+)](i) and contraction. In the presence of isoproterenol, the regional increase in [K(+)](o) induced sustained arrhythmias in 10 of 14 trabeculae, whereas the global increase did not induce such arrhythmias. During sustained arrhythmias, Ca(2+) surged within the jet-exposed region. In the absence of isoproterenol, the regional increase in [K(+)](o) increased Ca(CW), whereas the global increase decreased it. This increase in Ca(CW) with the regional increase in [K(+)](o) was not suppressed by 100 μmol/l streptomycin, whereas it was suppressed by 1) a combination of 10 μmol/l cilnidipine and 3 μmol/l SEA0400; 2) 20 mmol/l 2,3-butanedione monoxime; and 3) 10 μmol/l blebbistatin. A regional but not a global increase in [K(+)](o) induces sustained arrhythmias, probably due to nonuniform excitation-contraction coupling. The same mechanism may underlie arrhythmias during ischemia.
AJP Heart and Circulatory Physiology 03/2012; 302(11):H2301-9. · 3.71 Impact Factor
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ABSTRACT: A 52-year-old man was given a diagnosis of ulcerative colitis and treated with mesalazine for 7.5 years. However, the unusually long administration of mesalazine induced lung injury and the patient complained of a dry cough and dyspnea on limited exertion. Infiltrative shadows were observed in bilateral lung fields on a chest radiograph and computed tomographic images. The histological findings obtained by transbronchial biopsy and bronchoalveolar lavage showed organizing pneumonia. His drug-induced lymphocyte stimulation test (DLST) for mesalazine was positive. Improvements in his clinical symptoms and radiographic abnormalities occurred spontaneously after the discontinuation of mesalazine. This case indicates that the long-term administration of mesalazine may lead to an adverse pulmonary reaction.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 11/2011; 49(11):861-6.
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ABSTRACT: Although oxitropium bromide is used clinically as an anticholinergic drug (i.e., parasympathetic antagonist) to relax airway smooth muscle, we examined whether it has or does not have any effects on diaphragm muscle.
Three treatment sets, an oxitropium bromide inhalation only group, an oxitropium bromide inhalation plus endotoxin injection group (in vivo) and an oxitropium bromide incubation group (in vitro) were studied as to diaphragm muscle contractile properties.
Oxitropium bromide inhalation shifted force-frequency curves upward at 2 h after inhalation (p < 0.05) and inhibited the decrease of force-frequency curves due to endotoxin injection in vivo. Incubation with oxitropium bromide of untreated diaphragm muscle and diaphragm muscle injected with endotoxin did not increase the force-frequency curves dose-dependently in vitro; however, it caused both types of muscle to be fatigue resistant.
We speculate that the increment of muscle contractility with the inhalation of oxitropium bromide was induced by the antagonization of musucarinic acetylcholine receptors (mAChR). In addition, the changes of fatigue resistance provoked by oxitropium bromide, which also is speculated to antagonize mAChR, may be beneficial in the treatment of patients with COPD.
Allergology International 05/2011; 60(3):365-72.
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ABSTRACT: Triggered arrhythmias arise from delayed afterdepolarizations (DADs), with Ca(2+) waves playing an important role in their formation. In ventricular hypertrophy, however, it remains unclear how Ca(2+) waves change their propagation features and affect arrhythmogenesis. We addressed this important issue in a rat model of hypertrophy.
Rats were given a subcutaneous injection of 60 mg/kg monocrotaline (MCT-rats) or solvent (Ctr-rats). After 4 weeks, MCT-rats showed high right ventricular (RV) pressure and RV hypertrophy. Trabeculae were dissected from 36 right ventricles. The force was measured using a silicon strain gauge and regional intracellular Ca(2+) ([Ca(2+)](i)) was determined using microinjected fura-2. Reproducible Ca(2+) waves were induced by stimulus trains (2 Hz, 7.5s). MCT-rats showed a higher diastolic [Ca(2+)](i) and faster and larger Ca(2+) waves (P<0.01). The velocity and amplitude of Ca(2+) waves were correlated with the diastolic [Ca(2+)](i) both in the Ctr- and MCT-rats. The velocity of Ca(2+) waves in the MCT-rats was larger at the given amplitude of Ca(2+) waves than that in the Ctr-rats (P < 0.01). The amplitude of DADs was correlated with the velocity and amplitude of Ca(2+) waves in the Ctr- and MCT-rats.
The results suggest that an increase in diastolic [Ca(2+)](i) and an increase in Ca(2+) sensitivity of the sarcoplasmic reticulum Ca(2+) release channel accelerate Ca(2+) waves in ventricular hypertrophy, thereby causing arrhythmogenesis.
Circulation Journal 04/2011; 75(6):1343-9. · 3.77 Impact Factor
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ABSTRACT: Arrhythmias are benign or lethal, depending on their sustainability and frequency. To determine why lethal arrhythmias are prone to occur in diseased hearts, usually characterized by nonuniform muscle contraction, we investigated the effect of nonuniformity on sustainability and frequency of triggered arrhythmias.
Force, membrane potential, and intracellular Ca(2+) concentration ([Ca(2+)](i)) were measured in 51 rat ventricular trabeculae. Nonuniform contraction was produced by exposing a restricted region of muscle to a jet of 20 mmol/L 2,3-butanedione monoxime (BDM) or 20 mumol/L blebbistatin. Sustained arrhythmias (>10 seconds) could be induced by stimulus trains for 7.5 seconds only with the BDM or blebbistatin jet (100 nmol/L isoproterenol, 1.0 mmol/L [Ca(2+)](o), 24 degrees C). During sustained arrhythmias, Ca(2+) surges preceded synchronous increases in [Ca(2+)](i), whereas the stoppage of the BDM jet made the Ca(2+) surges unclear and arrested sustained arrhythmias (n=6). With 200 nmol/L isoproterenol, 2.5 mmol/L [Ca(2+)](o), and the BDM jet, lengthening or shortening of the muscle during sustained arrhythmias accelerated or decelerated their cycle in both the absence (n=10) and presence (n=10) of 100 mumol/L streptomycin, a stretch-activated channel blocker, respectively. The maximum rate of force relaxation correlated inversely with the change in cycle lengths (n=14; P<0.01). Sustained arrhythmias with the BDM jet were significantly accelerated by 30 mumol/L SCH00013, a Ca(2+) sensitizer of myofilaments (n=10).
These results suggest that nonuniformity of muscle contraction is an important determinant of the sustainability and frequency of triggered arrhythmias caused by the surge of Ca(2+) dissociated from myofilaments in cardiac muscle.
Circulation 06/2010; 121(25):2711-7. · 14.74 Impact Factor
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ABSTRACT: Tulobuterol, a sympathomimetic drug used as a transdermal patch, increases normal diaphragm muscle strength. Because diaphragm muscle weakness (i.e. decrease of contraction) is a feature of bronchial asthma and sepsis, we examined the in vitro and in vivo effects of tulobuterol on the contractility of diaphragm muscles prepared from mice treated with endotoxin. We measured contractile parameters of force-frequency curves and twitch kinetics using untreated or treated diaphragm muscles at 0 (E0) and 4 (E4) hours after E. coli endotoxin (20 mg/kg) administration. The force-frequency curve of E4 diaphragm muscle was decreased from that of E0 diaphragm muscle (p < 0.001). E4 diaphragm muscle was incubated in an organ buffer containing 10(-7) or 10(-5) M concentrations of tulobuterol for 1 h (in vitro). The force-frequency curves of both 10(-7) (p < 0.01) or 10(-5) M (p < 0.001) tulobuterol concentrations shifted significantly upward from those of no tulobuterol, indicating that tulobuterol can recover the diaphragm muscle contractility that was decreased by endotoxin. In the in vivo treatment, E0 and E4 diaphragm muscles were analyzed at 0, 12, and 24 h after transdermal tulobuterol treatment. The force-frequency curves of E0 and E4 diaphragm muscles at three time points were not significantly changed each other, indicating that tulobuterol patch restores the muscle contractility. Thus, diaphragm muscle contractility was maintained during 4 h of endotoxin administration with tulobuterol patch for over 24 h. We suggest that this treatment of bronchial asthma may protect against endotoxin contained in inhaled house dust.
The Tohoku Journal of Experimental Medicine 08/2009; 218(4):271-8. · 1.24 Impact Factor
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ABSTRACT: Although procaterol is used clinically as a beta(2)-adrenergic receptor agonist to relax airway smooth muscle, it has not yet been clarified whether procaterol has inotropic effects on respiratory muscles.
Three intervention groups were investigated: a procaterol inhalation only group; a procaterol inhalation plus endotoxin injection group (in vivo); and a procaterol incubation group (in vitro). The diaphragm muscle in all groups was dissected and measurements of its contractile properties were performed.
The effects of procaterol inhalation shifted the force-frequency curves upward at 30 minutes after inhalation, and inhibited the decline of force-frequency curves due to endotoxin injection in vivo. In vitro administration of procaterol resulted in an increase in the force-frequency curves in a dose-dependent manner.
It can be concluded that procaterol has an inotropic effect on the diaphragmatic muscles taken from normal animals as well as on the diaphragm muscles in a septic animal model.
Allergology International 10/2007; 56(3):285-91.
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ABSTRACT: Clinically, patients suffering from bronchial asthma are often treated transdermally with tulobuterol patches to dilate the bronchi. Tulobuterol, a synthetic beta(2) agonist, is also thought to act as a diaphragm muscle contractor, like other beta(2) sympathomimetic drugs. However, it has not been clarified that transdermal treatment with tulobuterol influences diaphragm muscle contractility. We therefore examined its effects on contractile properties of such muscles obtained from BALB/c mice. Two systems, a tulobuterol incubation group (in vitro) and a tulobuterol transdermal treatment group (in vivo), were employed. In both groups, the contractile properties of the dissected diaphragm muscles were measured by field stimulation in an organ bath. In the incubation group, the diaphragm muscle of untreated mice was incubated in an organ buffer at 10(-7), 10(-6), or 10(-5) M tulobuterol for 1 hr and then measured for contractility. Tulobuterol significantly increased force-frequency curves at a concentration of 10(-5) M at 1 (p < 0.01), 30, 50, 70, 100, and 120 Hz (p < 0.05, each) compared with the values at 0 M. In the transdermal treatment group, the diaphragm muscle was dissected from animals at 1, 4, 8, 12, or 24 hrs after treatment and measured for contractility, showing that the force-frequency curves were significantly increased and maintained from 4 to 24 hrs (each p < 0.01 as compared with the sham-treated group). We suggest that transdermal tulobuterol treatment in case of bronchial asthma is useful not only for bronchial dilatation, but also for increasing diaphragm muscle contractility.
The Tohoku Journal of Experimental Medicine 07/2007; 212(3):309-17. · 1.24 Impact Factor
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ABSTRACT: To find predicted values of respiratory function tests in young persons in Japan, we measured slow vital capacity and forced vital capacity in 1,141 subjects aged from 10 to 20 years. The values obtained from 636 persons (363 males and 273 females) who were not smokers or had no suspected rhinitis or asthma were analyzed. Although FEV1% by the Gaensler and Tiffeneau methods were almost constant regardless of age, all other values of respiratory function tests increased with age and then reached a plateau level in late teens. Excluding the Gaensler and Tiffeneau FEV1%, in a single regression analysis using gender, age, and height, both the contribution ratio and regression coefficient were the highest using height, followed by age. In addition, the result was similar with multiple regression analysis. Therefore, for a young person aged from 10 to 20 years, body height is the most important predictor variable of respiratory function tests, compared to gender and age. For each respiratory function test, we showed the prediction relation according to gender obtained from multiple linear regression analysis using 2 variables of height and age.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 01/2007; 44(12):916-22.
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ABSTRACT: Patients with severe pulmonary emphysema have a greatly increased oxygen cost of breathing (O(2) cost), and this is the cause of serious malnutrition, or respiratory cachexia, in such patients.
To clarify the effect of lung volume reduction surgery (LVRS) on respiratory function and the nutritional state of these patients through a reduction in the O(2) cost of the respiratory muscles.
Prospective cohort study. Setting, patients, and interventions: Twenty-three patients who underwent LVRS in Tohoku University Hospital.
Pulmonary function and O(2) cost were measured perioperatively by utilizing a method of continuous dead space. In addition, we calculated the proportion of oxygen consumption (O(2)) of respiratory muscles to total O(2) (%O(2)resp) from the measured energy expenditure and the predicted values.
FEV(1) and arterial oxygen pressure increased after surgery while lung volume and dyspnea decreased (p < 0.01), and O(2) cost was also reduced from 0.044 to 0.026 log(mL/min)/(L/min) [p < 0.001]. Moreover, the change in O(2) cost had a strong negative correlation with that of FEV(1) (r = - 0.70, p < 0.001), and a moderate positive correlation with that of the ratio of residual volume to total lung capacity (r = 0.54, p < 0.01). %O(2)resp was 23.1% at rest and 55.5% at maximal ventilation. LVRS reduced %O(2)resp at maximal ventilation to 49.0% (p < 0.05), but %O(2)resp at rest did not decrease after surgery.
LVRS reduces energy expenditure of respiratory muscles especially during exercise by decreasing small airway obstruction and hyperinflated lung volume. This may reverse the malnourished state in end-stage emphysema.
Chest 06/2003; 123(6):1847-52. · 5.25 Impact Factor
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ABSTRACT: To evaluate the role of interleukin (IL)-18 in endotoxin-induced diaphragm muscle deterioration, we studied three treatment groups, namely, a saline+endotoxin group, an IL-18+endotoxin group and an IL-18 only group using Wistar rats. Five minutes after saline or IL-18 (0.25 microg) injection, E. coli endotoxin (30 mg/kg) was injected intraperitoneally. In the saline+endotoxin group, the force-frequency curves by ANOVA (p < 0.01), twitch tension (TT) and slope during contraction time (TT/CT) were significantly lower at 4 hours than those at 0 hours due to endotoxin (p < 0.01 and p < 0.05, respectively) and nitric oxide (NO) production had increased at 4 hours as shown by NADPH diaphorase staining. In the IL-18+endotoxin group, the decrement of the force-frequency curves in a higher frequency range (50-120 Hz), and the decrements of TT and TT/CT observed at 4 hours in the saline+endotoxin group were significantly prevented, and NO production was blocked at 4 hours. In the IL-18 only group, the force-frequency curves did not change except for fatigability, and NO production did not occur. It is suggested that IL-18 itself naturally blocks NO production, even when endotoxin coexists, resulting in the prevention of deterioration of diaphragm muscle contraction by endotoxin.
The Tohoku Journal of Experimental Medicine 04/2002; 196(4):269-80. · 1.24 Impact Factor
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ABSTRACT: We performed a transsubxiphoidal LV puncture (TSLVP) to evaluate left ventricular function in 21 patients with both mechanical prosthetic aortic and mitral valves and successfully obtained hemodynamic information on each patient. Analyzing cardiac hemodynamic information and ventriculographic findings obtained with TSLVP, we concluded that seven of the patients required repair of their prosthetic valves. Five of these seven patients agreed to replacement of their valves, whereas two did not. TSLVP was performed adequately and safely without severe complications, suggesting that this maneuver is easier than that of transapical LV puncture and should be recommended for the assessment of left ventricular hemodynamic functions instead of the transapical LV puncture, especially in patients requiring replacement of two valves.
Catheterization and Cardiovascular Interventions 02/2002; 55(1):58-65. · 2.29 Impact Factor
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ABSTRACT: The effects of an intravenous injection of Interleukin-12 (IL-12) after endotoxin administration and without endotoxin administration on diaphragm muscle were studied using Wistar rats. Three treatment groups, namely a control (Saline+endotoxin) group, an IL-12+endotoxin group and an IL-12 only group were studied. E. coli endotoxin (30 mg/kg) was injected intraperitoneally 5 min after Saline or IL-12 (0.25 μg) injection. In the control group, the force–frequency curves, twitch tension (TT) and slope during contraction time (TT/CT) were significantly lower at 4 h than those at 0 h due to endotoxin (P<0.001, P<0.01 and P<0.01, respectively), and NO production was increased at 4 h as shown by NADPH diaphorase staining. In the IL-12+endotoxin group, the decrement of the force–frequency curves, TT and TT/CT induced by endotoxin at 4 h were significantly prevented compared with those of the control group (P<0.001, P<0.05 and P<0.05, respectively), and NO production was blocked at 4 h. In the IL-12 only group, the force–frequency curves were decreased in the range of high frequency and IL-12 resulted in NO production. Furthermore, the positive muscle fibers detected by NADPH diaphorase staining were classified as type I and IIa muscle fibers by ATPase staining in the control and IL-12 only groups. It is concluded that IL-12 prevents the deterioration of diaphragm muscle contraction induced by endotoxin by reducing NO production in type I and IIa muscle fibers. These results suggest that IL-12 and endotoxin may interfere with each other.
Comparative Biochemistry and Physiology - Part A: Molecular & Integrative Physiology.
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