Biomedical subjects

H Tomoike

Publications and source records attributed to H Tomoike.

At least 19 recordsLinked to original sources

PubMed1997

Serum levels of soluble form of Fas molecule in patients with congestive heart failure.

Compared with soluble Fas molecule (sFas, an inhibitor of Fas-mediated apoptosis) in normal volunteers, the serum level of sFas significantly increased by 41% in New York Heart Association (NYHA) class III (p <0.05) and by 97% in NYHA class IV patients with congestive heart failure (p <0.001). Furthermore, sFas showed correlations with soluble forms of TNF receptor-p55 (RI) and -p75 (RII) (r = 0.68 and r = 0.56) which inhibit activities of TNF alpha.

Adult↗

PubMed1997

Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.

BACKGROUND: Familial long-QT syndrome (LQTS) is characterized by prolonged ventricular repolarization. Clinical symptoms include recurrent syncopal attacks, and sudden death may occur due to ventricular tachyarrhythmias. Three genes responsible for this syndrome (KVLQT1, HERG, and SCN5A) have been identified so far. We investigated mutations of these genes in LQTS families. METHODS AND RESULTS: Thirty-two Japanese families with LQTS were brought together for screening for mutations. Genomic DNA from each proband was examined by the polymerase chain reaction-single-strand conformation polymorphism technique followed by direct DNA sequencing. In four of the families, comprising 16 patients, mutations were identified in KVLQT1; five other families (9 patients) segregated mutant alleles of HERG. All 25 of these patients carried the specific mutations present in their respective families, and none of 80 normal individuals carried these alleles. Mutations were confirmed by endonuclease digestion or hybridization of mutant allele-specific oligonucleotides. No mutation in SCN5A was found in any family. CONCLUSIONS: We identified nine different mutations among 32 families with LQTS. Eight of these were novel and account for 25% of all types of mutations reported to date. Such a variety of mutations makes it difficult to screen high-risk groups using simple methods such as endonuclease digestion or mutant allele-specific amplification.

Alleles↗

PubMed1997

Elevated levels of type II soluble tumor necrosis factor receptors in the bronchoalveolar lavage fluids of patients with sarcoidosis.

Since tumor necrosis factor (TNF) is known to be involved in granuloma formation in sarcoidosis, and soluble TNF receptors (sTNF-Rs) inhibit TNF action in vivo, we evaluated the levels of sTNF-Rs in the bronchoalveolar lavage fluids (BALF) of 31 subjects using an enzyme-linked immunosorbent assay. Our group consisted of 13 patients with sarcoidosis (7 sarcoidosis patients who received no treatment and 6 who received corticosteroid therapy) and 18 control subjects (11 healthy nonsmokers and 7 asymptomatic smokers). Type II (75-kDa), but not type I (55 kDa) sTNF-R in BALF was elevated significantly in patients with sarcoidosis compared with the healthy nonsmokers (type I: 126.7 +/- 17.6 pg/ml BALF vs 79.4 +/- 16.5 pg/ml BALF, p > 0.05; type II: 98.3 +/- 27.8 pg/ml BALF vs 26.7 +/- 4.9 pg/ml BALF, p < 0.05). Although levels of type I sTNF-R in BALF from sarcoidosis patients were not correlated with any cellular profiles of BALF, concentrations of type II correlated significantly with the numbers of lymphocytes in BALF. We concluded that sTNF-R is a normal constituent of the epithelial lining fluids and that levels of type II sTNF-R are elevated significantly in the BALF from individuals with sarcoidosis. This suggests that sTNF-Rs may influence the local bioactivity of TNF and may also contribute to the pathogenesis of sarcoidosis.

Antigens, CD↗

PubMed1997

Effects of activation sequence on monophasic action potential configuration in the dog.

The effects of altered activation sequence on the monophasic action potential (MAP) in in situ beating hearts are not known, although its effects on refractory periods are well documented. In nine anesthetized, open-chest dogs, complete atrioventricular block was produced, and the heart was driven by either right ventricular or left ventricular stimulation. The MAPs of the right and left ventricles were recorded by contact electrodes at cycle lengths of 1,000, 800, 600, and 400 ms. The MAP configuration was evaluated with regard to the difference between phase 1 and phase 2 MAP amplitudes and MAP duration at 50 and 90% repolarization. An MAP recorded from the ventricle that was being electrically stimulated was designated an ipsilateral ventricular stimulation, whereas the MAP recorded from the nonstimulated ventricle was termed a contralateral ventricular stimulation. The difference in amplitude and the 50% and 90% MAP durations for ipsilateral ventricular stimulation were consistently larger than for contralateral ventricular stimulation at all cycle lengths tested. Transient outward current did not appear to play a major role in producing such differences in MAP because intravenous treatment with 4-aminopyridine, a blocker of transient outward current, did not affect the configuration of the MAP. These findings provide an insight on the influence of ventricular activation sequence on the shape of the transmembrane action potential.

4-Aminopyridine↗

PubMed1997

Electrophysiologic effects of sodium channel blockade on anisotropic conduction and conduction block in canine myocardium: preferential slowing of longitudinal conduction by flecainide versus disopyramide or lidocaine.

OBJECTIVES: The purpose of this study was to determine the effects of sodium channel blockade on anisotropic excitation propagation in the intact canine left ventricle. BACKGROUND: Anisotropic ventricular conduction- electric conductivity dependent on the myocardial fiber direction-is one of the important mechanisms of ventricular arrhythmia. However, the effects of sodium channel blockade, especially the differential effect of a subclass of this agent, on the anisotropic properties remain unknown. METHODS: In 28 anesthetized, open chest dogs, a small cannula was inserted into the left anterior descending coronary artery. Saline (control), disopyramide, lidocaine or flecainide was infused selectively into the cannula. An array of 64 epicardial electrodes was placed on the anterior surface of the ventricle. Activation time (AT) was measured along the longitudinal (L) and transverse (T) directions. RESULTS: High dose flecainide (100 microg/kg body weight per min) delayed the AT along the L direction markedly (mean [+/-SE] 227 +/- 38%, p < 0.02) and mildly (121 +/- 10%, p < 0.02) along the T direction in regular beats (p < 0.007, L vs. T). Lidocaine and disopyramide did not show direction-dependent prolongation of the AT on regular beats. When examined on premature beats, AT was delayed, depending on the coupling interval and the fiber direction when saline, flecainide or lidocaine was infused. The conduction blocks along the L direction were observed in three of seven dogs on regular beats after flecainide and ventricular fibrillation ensued in two of these three dogs. CONCLUSIONS: A peculiar slowing of L conduction by flecainide may relate to the character of proarrhythmia.

Animals↗

PubMed1997

Visualisation of exercise-induced ischaemia of the right ventricle by thallium-201 single photon emission computed tomography.

OBJECTIVE: Exercise thallium-201 (201T1) single photon emission computed tomography (SPECT) has been used to detect potential ischaemia in the left ventricular myocardium but not in the right ventricle. The purpose of this study was to establish the clinical usefulness of a right ventricular polar map of 201T1 SPECT for visualisation of exercise-induced right ventricular ischaemia. METHODS: Myocardial 201T1 SPECT was obtained immediately after treadmill exercise in 97 patients with suspected coronary artery disease. A region of interest was placed over the right ventricle (RV) on post-stress transaxial images. Short axis images of this region were generated and reconstructed as a bull's eye polar map. Normal ranges of RV 201T1 uptake were determined in 12 patients with normal coronary arteries. Scintigraphic criteria for identifying RV perfusion abnormality were derived from 25 patients with right coronary artery (RCA) stenosis greater than 75%. These criteria were applied to 60 consecutive patients with suspected coronary artery disease. RESULTS: Perfusion defects in the RV were larger in patients with proximal RCA stenosis than in those with distal RCA stenosis (mean (SD) 28 (16)% v 6 (5)%, P < 0.001). The sensitivity and specificity of the RV polar map for the detection of proximal RCA stenosis were 67% (8/12) and 98% (47/48), respectively. RV perfusion defects became undetectable in 9 patients who had successful percutaneous transluminal coronary angioplasty to a proximal RCA lesion. CONCLUSIONS: A right ventricular polar map display was useful for visualising exercise-induced right ventricular ischaemia.

Adult↗

PubMed1997

Inhibition of neutrophil elastase-induced interleukin-8 gene expression by urinary trypsin inhibitor in human bronchial epithelial cells.

BACKGROUND: Urinary trypsin inhibitor (UTI), a potential inhibitor for proteinases including neutrophil elastase (NE), trypsin, plasmin, cathepsin B and H has been used for the treatment of lung diseases with the absence of side effects in Japan. METHODS: In this study, we investigated the inhibitory effects of UTI on both purified NE and NE activities present in bronchoalveolar fluids from patients with chronic bronchitis. We also investigated the inhibitory capacity of UTI with regard to NE-induced interleukin-8 gene expression in human bronchial epithelial cells by Northern analyses. RESULTS: UTI inhibited NE activities in bronchoalveolar lavage fluid from patients with chronic bronchitis and of the purified enzyme. In addition, UTI inhibited NE-induced interleukin-8 gene expression and protein secretion in a human bronchial epithelial cell line. CONCLUSIONS: Our results suggest that UTI is applicable to patients with a variety inflammatory lung diseases in which NE plays a pivotal role.

Bronchi↗

PubMed1997

Elevated levels of cytokeratin 19 in the bronchoalveolar lavage fluid of patients with chronic airway inflammatory diseases--a specific marker for bronchial epithelial injury.

Cytokeratin 19 (CK19) is a specific cytoskeletal structure of simple epithelia, including bronchial epithelial cells (BEC). Since CK19 is released from injured bronchial epithelium, we investigated the levels of CK19 fragments in the bronchoalveolar lavage fluid (BALF) of eight patients with chronic airway inflammatory diseases (CAID) using an enzyme-linked immunosorbent assay (ELISA). Included in our test group were four cases of chronic bronchitis, three cases of bronchiectasis, and one case of diffuse panbronchiolitis. There were also 15 control subjects (five asymptomatic smokers and 10 nonsmokers). BALF from the nonsmokers as well as from the asymptomatic smokers contained few CK19 fragments (0.2 +/- 0.2 and 1.9 +/- 0.8 pg/ml, respectively). In contrast, significantly high levels of CK19 were present in the BALF of patients with CAID (21.7 +/- 5.7 pg/ml; p < 0.01 versus nonsmoking controls). In addition, CK19 fragment concentrations in BALF correlated significantly with the number of neutrophils (r = 0.722, p < 0.01) but not with the numbers of macrophages or lymphocytes in BALF. BALF from patients with CAID contained high levels of neutrophil elastase (NE) activity, suggesting that NE might be an important stimulus for the release of CK19 from BEC. To prove this, we incubated BET-1A cells, a human immortalized bronchial epithelial cell line, both in the absence and the presence of inflammatory mediators (including NE, tumor necrosis factor-alpha [TNF-alpha], and hydrogen peroxide). We then measured the concentration of CK19 fragments in the culture supernatants with ELISA. BET-1A cells released CK19 fragments into their culture supernatants after treatment with NE but not after treatment with TNF or hydrogen peroxide. Further, we demonstrated that CK19 cleaved by NE could not be detected by ELISA. Our results suggest that CK19 measurement in BALF is useful for assessing the presence of bronchial epithelial injuries.

Adult↗

PubMed1997

Roles of nitric oxide and adenosine in the regulation of coronary conductance in the basal state and during reactive hyperemia.

Nitric oxide (NO) and adenosine are important mediators in the regulation of coronary vascular tone and are released into the interstitium from the vascular endothelium and myocardium, respectively. The roles of these autacoids in the regulation of coronary flow in the basal and reactive hyperemic states were examined in Langendorff rabbit hearts perfused with oxygenated Krebs-Henseleit solution at 37 degrees C and 110 mmHg pressure. Instantaneous perfusion pressure-flow relationships were analyzed to derive coronary conductance both in the basal state and during the early phase of reperfusion (hyperemic state). N omega-nitro-L-arginine methyl ester (L-NAME) at increasing concentrations (10(-6) to 10(-4) mol/L) (n = 7) and 8-phenyltheophylline (8-PT) at increasing concentrations (10(-9) to 10(-6) mol/L) (n = 7) were applied to assess the role of NO and adenosine, respectively. L-NAME dose-dependently reduced the coronary conductance in both the basal and early hyperemic states, while 8-PT dose-dependently reduced conductance only in the hyperemic state. Changes in conductance during the early hyperemic phase correlated well with changes in the debt repayment ratio for either L-NAME (r = 0.94) or 8-PT (r = 0.99). These data suggest that a flow-related NO release mechanism regulates the coronary conductance in both the basal and hyperemic states while the metabolic regulation of adenosine release plays a role in the presence of ischemia.

Adenosine↗

PubMed1997

Fatty acid metabolic imaging with iodine-123-BMIPP for the diagnosis of coronary artery disease.

UNLABELLED: Iodine-123-BMIPP kinetics under high glucose levels were examined. The feasibility of 123I-BMIPP imaging after oral glucose loading for the detection of impaired fatty acid metabolism was tested in patients with coronary artery disease. METHODS: Fatty acid metabolic imaging with 123I-BMIPP was performed on 29 patients in the fasting state and repeated after oral glucose loading. Myocardial SPECT images were obtained 20 min and 4 hr after the injection of 123I-BMIPP. Myocardial uptake of 123I-BMIPP was calculated by a Ishii-Macintyre method and the clearance of 123I-BMIPP from the myocardium was determined as (early counts-delayed counts) x 100/early counts. Regional accumulation of 123I-BMIPP was scored semiquantitatively from 0 (normal) to 4 (no activity), and the sum of regional scores in each patient was defined as a total defect score (TDS). RESULTS: Total myocardial uptake of 123I-BMIPP was 1.7% +/- 0.4% in the fasting state and 1.6% +/- 0.3% after oral glucose loading (p < 0.05). Iodine-123-BMIPP clearance from the myocardium was faster after glucose loading than in the fasting state (27% +/- 8% versus 11% +/- 6%, p < 0.01). After glucose loading, 123I-BMIPP clearance was faster in the ischemic myocardium (defined as areas perfused by stenosed coronary artery exceeding 90%) than in the nonischemic myocardium (33% +/- 8% versus 25% +/- 9%, p < 0.05). TDS in the ischemic myocardium increased from 1.8 +/- 0.4 in the fasting state to 2.1 +/- 0.4 after glucose loading (p < 0.01). The sensitivity for detecting coronary stenosis exceeding 90% increased from 55% (11/20) in the fasting state to 75% (15/20) after glucose loading without a loss of specificity (78%, 7/9). CONCLUSION: Oral glucose loading enhanced the detection of areas with impaired fatty acid metabolism due to coronary artery narrowing. Iodine-123-BMIPP imaging with oral glucose loading may be a new approach for the noninvasive diagnosis of coronary artery disease.

Adult↗

PubMed1997

ACE inhibition reduces cardiac iodine-123-MIBG release in heart failure.

UNLABELLED: Radioiodinated metaiodobenzylguanidine (123I-MIBG), an analog of norepinephrine, has been used to assess cardiac sympathetic nerve activity. Decreased myocardial accumulation and enhanced washout of 123I-MIBG have been reported in patients with congestive heart failure (CHF). The purpose of this study was to determine whether angiotensin converting enzyme (ACE) inhibition reduced 123I-MIBG release and improved cardiac 123I-MIBG accumulation in patients with CHF. METHODS: Twenty-nine patients receiving conventional treatment for CHF, New York Heart Association (NYHA) functional class 2-3, were studied. Nineteen patients received additional treatment with enalapril, an ACE inhibitor, and 10 patients who were treated with conventional therapy alone were defined as a control group. Iodine-123-MIBG imaging and echocardiography were performed on all patients before treatment and repeated after 9.1 +/- 3.0 mo of treatment. Images were obtained 30 min and 4 hr after injection of 123I-MIBG, and a heart to mediastinum (H/M) ratio was defined to quantify cardiac 123I-MIBG uptake as a fraction of the mean counts per pixel in the heart divided by those in the mediastinum. The washout rate of 123I-MIBG from the heart was calculated as follows: (early counts - delayed counts)/early counts x 100(%). RESULTS: In patients with enalapril group, the H/M ratio of 123I-MIBG was increased after treatment (early image: 1.60 +/- 0.22 vs. 1.73 +/- 0.28, p < 0.05, delayed image: 1.63 +/- 0.28 vs. 1.82 +/- 0.33, p < 0.01). The washout rate of 123I-MIBG was reduced from 38% +/- 11% to 30% +/- 12% after treatment (p < 0.01). However in the conventional therapy group, the H/M ratios in the early and delayed images (early image: 1.58 +/- 0.31 vs. 1.52 +/- 0.23, delayed image: 1.49 +/- 0.27 vs. 1.49 +/- 0.25) and the washout rate (34% +/- 8% vs. 33% +/- 7%) remained unchanged after treatment. In patients with an increased H/M ratio of enalapril group (n = 13), a left ventricular ejection fraction increased from 48% +/- 12% to 55% +/- 9% (p < 0.01) after treatment. CONCLUSION: ACE inhibition reduces cardiac 123I-MIBG release and thus lowers cardiac sympathetic nerve activity. Iodine-123-MIBG may be helpful in evaluating the therapeutic effects of ACE inhibition on the cardiac sympathetic nervous system in patients with CHF.

3-Iodobenzylguanidine↗

PubMed1996

Immunolocalization of an inwardly rectifying K+ channel, K(AB)-2 (Kir4.1), in the basolateral membrane of renal distal tubular epithelia.

Immunolocalization of K(AB)-2 (Kir4.1), an inwardly rectifying K+ channel with a putative ATP-binding domain, was examined in rat kidney where expression of K(AB)-2 mRNA was previously shown. Anti-K(AB)-2 antibody was raised in rabbit and then affinity-purified. An immunohistochemical study revealed that K(AB)-2 immunoreactivity was detected specifically in the basolateral membrane of distal tubular epithelia. Therefore, K(AB)-2 is the first K+ channel shown to be localized in the basolateral membrane of renal epithelia. The finding suggests that K(AB)-2 may contribute to supplying K+ to the Na(+)-K+ pump, which is abundant in the basolateral membrane of distal tubular epithelia, as well as to maintenance of the deep negative membrane potential of these cells.

Amino Acid Sequence↗

PubMed1996

Cellular detachment and deformation induce IL-8 gene expression in human bronchial epithelial cells.

Neutrophil elastase (NE) is known to be one of the most potent proteases capable of deforming and detaching human bronchial epithelial cells (BECs) and inducing IL-8 gene expression. However, mechanisms of NE-induced IL-8 gene expression are unclear, especially with respect to how they relate to cellular detachment. To elucidate these mechanisms, effects of cell detachment and deformation following mechanical injury or pharmacologic stimuli on IL-8 gene expression were examined by Northern analyses. When BET-1A cells from a human bronchial epithelial cell line were incubated with NE (100 nM), trypsin (0.5 mg/ml), EGTA (7 mM), or EDTA (0.7 mM) to induce deformation and detachment, IL-8 mRNA transcript levels were up-regulated, as demonstrated in a case of mechanical detachment from the culture plate using a cell scraper. This IL-8 gene expression was inhibited by pretreatment with 5 microM taxol, a microtubule-stabilizing agent. Colchicine or vinblastine, microtubule-disrupting agents, induced IL-8 gene expression, which was also inhibited by taxol treatment. These data suggest that structural changes, including deformation of the cytoskeleton, especially microtubules, may contribute to IL-8 gene expression in human BECs. Since detachment and cellular deformation of BECs caused by proteases have been observed frequently in a variety of inflammatory airway diseases, our findings provide evidence that detached or deformed BECs potentially enhance production of inflammatory mediators in the pathogenesis of airway inflammation.

Base Sequence↗

PubMed1996

Glibenclamide attenuates peaked T wave in early phase of myocardial ischemia.

OBJECTIVES: ECG peaked T wave appears during the early phase of myocardial ischemia, but the underlying mechanisms remain unknown. The purpose of this study was to elucidate the role of ATP-sensitive K+ channel (KATP) in this ECG change. METHODS: In 12 anesthetized, open-chest dogs, the sinus node was crushed and the right atrium was paced at a cycle length of 400 ms. The left anterior descending coronary artery was abruptly occluded for 60 s before (control) and 15 min after an intravenous infusion of vehicle (n = 6) or glibenclamide (1 mg/kg, n = 6), a blocker of KATP. Forty-eight epicardial electrograms were simultaneously recorded from the anterior surface of the left ventricle. The potentials at 40, 80 and 120 ms from the J point were measured, and these points corresponded to the early, middle and late phases of the T wave, respectively. RESULTS: During the control occlusion, T wave increased time-dependently and the maximal T-wave change was noted at the end of 60 s of coronary occlusion. The extents of T-wave elevation at the early, mid and late T phases were 5.5 +/- 0.5, 7.3 +/- 0.8 and 11.7 +/- 1.8 mV, respectively, and these T-wave elevations were significantly reduced by 33 +/- 21%, 59 +/- 12% and 63 +/- 13%, respectively, after the pretreatment with glibenclamide but not with its vehicle. The % reductions of mid and late T by glibenclamide were significantly larger than that of early T wave (P < 0.05). CONCLUSIONS: An abrupt coronary occlusion accompanied peaked T wave as an early ECG wave change. As the extent of this T-wave elevation was attenuated by glibenclamide, the ischemia-induced alteration of ventricular repolarization can partly (60%) be explained by the modification of KATP activation.

Adenosine Triphosphate↗

PubMed1996

Impaired hyperemic response of brachial artery with the presence of diabetes mellitus in patients with coronary artery disease: a preliminary study.

Microvascular reactivity was assessed in reactive hyperemic response of brachial artery in 10 patients with non-insulin-dependent diabetes mellitus and 34 non-diabetic patients. Each subject was diagnosed clinically as having angina pectoris and was examined by coronary angiography. Brachial arterial flow was determined by a pulsed Doppler velocity measurement, guided by a high-resolution B-mode imaging of the forearm. Peak systolic velocity at the basal state in diabetic and non-diabetic patients was comparable (0.53 +/- 0.03 versus 0.61 +/- 0.04 m/s, respectively; P = NS). The velocity ratio of the peak systolic flow at the basal state to the maximum velocity during hyperemia of 2 min arterial occlusion tended to be less in diabetic than in non-diabetic patients (1.76 +/- 0.14 versus 2.15 +/- 0.13, respectively; P = NS). The duration of hyperemic flow was less in diabetic than in non-diabetic patients (6.7 +/- 0.7 versus 9.9 +/- 0.6 s, respectively; P < 0.02). Such alterations in reactive hyperemia may be relevant to the microvascular disorder of the peripheral vessel in the presence of diabetes mellitus.

Aged↗

PubMed1996

Fatty acid metabolic imaging with 123I-BMIPP for the diagnosis of coronary artery disease: application to patients with diabetes mellitus and hyperlipidaemia.

The aim of this study was to assess the relation of plasma substrate concentration to 123I-beta-methyliodophenyl-pentadecanoic acid (123I-BMIPP) kinetics in the myocardium and to test the application of 123I-BMIPP imaging to patients with diabetes mellitus (DM) and/or hyperlipidemia (HL). 123I-BMIPP imaging was performed on 78 patients with suspected coronary artery disease, 22 with HL, 11 with DM, 12 with HL and DM, and 33 with neither HL or DM. Significant coronary stenosis (defined as > or = 50% of luminal diameter) was documented in 49 patients. After an overnight fast, blood samples were drawn for blood glucose, insulin, cholesterol, triglycerides and free fatty acid levels. Then, 148 MBq 123I-BMIPP was injected intravenously and flushed rapidly with saline. Data were obtained for 60s in a standard anterior projection in list mode, at a rate of 1 frame per second. Myocardial single photon emission tomographic (SPET) images were obtained 20 min and 4 h post-injection. The myocardial uptake of 123I-BMIPP was calculated using the Ishii-MacIntyre method. Regional accumulation of 123I-BMIPP was scored semi-quantitatively from 0 (normal) to 4 (no activity), and the sum of regional scores in each patient was defined as the total defect score (TDS). Myocardial uptake and clearance of 123I-BMIPP had no relation to the levels of blood glucose, insulin, cholesterol, triglycerides or free fatty acids. Myocardial uptake and clearance of 123I-BMIPP, TDS and the sensitivity of detecting significant coronary stenosis were not significantly different between the four groups of patients. We conclude that 123I-BMIPP can be used to detect impaired fatty acid metabolism in patients with diabetes mellitus and/or hyperlipidaemia.

Biological Transport, Active↗

PubMed1996

Ca2+ sensitizer Org-30029 reverses acidosis- and BDM-induced contractile depression in canine myocardium.

Effects of the Ca2+ sensitizer N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride (Org-30029) on the myocardial contractile depression induced by acidosis and 2,3-butanedione monoxime (BDM) were investigated in aequorin-loaded canine ventricular myocardium. The peak Ca2+ transient-peak force relation during administration of Org-30029 (10(-4) to 10(-3) M) was shifted to the left and upward compared with the relation for elevation of the extracellular Ca2+ concentration ([Ca2+]o) (2.5-12.5 mM). Acidosis (pH 6.6) depressed the force with a small increase in the peak Ca2+ transient. BDM (3 mM) depressed the force with no change in the peak and duration of the Ca2+ transient, indicating that BDM may inhibit selectively the cross-bridge interaction. During acidosis or in the presence of BDM, elevation of [Ca2+]o increased the peak Ca2+ transient to the same extent as that in the control, but the force was inhibited. In contrast, Org-30029 increased the force to a level equivalent to the control with a slight change in the peak Ca2+ transient. In addition, during acidosis, Org-30029 (10(-3) M) increased the force in association with a slight decrease in the peak Ca2+ transient. Thus Org-30029 can reverse the myocardial contractile depression induced by a decrease in the Ca2+ sensitivity of myofilaments, as occurs in pathophysiological situations such as acidosis in cardiac ischemia. Org-30029 may exert the Ca(2+)-sensitizing effect by an increase in the affinity of troponin C for Ca2+ and by a direct action on the cross-bridge interaction.

Acidosis↗

PubMed1996

Tumour necrosis factor receptor gene expression and shedding in human whole lung tissue and pulmonary epithelium.

This study aimed to investigate the expression of tumour necrosis factor receptor (TNF-R) at the gene and surface level, and its shedding in human lung tissue and a pulmonary epithelial cell line, A549. Levels of gene expression of TNF-R were evaluated by Northern blot analysis. Human lung tissue expressed both type I and type II TNF-R gene, while A549 cells expressed only type I TNF-R gene. Phorbol ester upregulated and TNF-alpha down-regulated the TNF-R gene expression in A549 cells. Consistent with these modulations of TNF-R gene expression, 125I-TNF binding capacities were increased with phorbol ester stimulation and decreased with TNF stimulation after 24 h in A549 cells. The shedding of TNF-R from A549 cells was investigated using enzyme-linked immunosorbent assay (ELISA) for soluble type I TNF-R. Not only lung tissues but also A549 cells spontaneously released soluble type I TNF-R into the culture medium. Both phorbol ester and TNF stimulation accelerated the shedding of soluble TNF-R from A549 cells. These results suggest that type I TNF-R gene expression and shedding of soluble TNF-R are differentially regulated in A549 cells. We conclude that tumour necrosis factor receptor surface expression is regulated, at least in part, at the gene expression level and shedding of soluble tumour necrosis factor receptor is modulated by inflammatory mediators, such as tumour necrosis factor in A549 cells.

Analysis of Variance↗