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T Shishido

Publications and source records attributed to T Shishido.

At least 55 records · Page 3Linked to original sources
PubMed2000

Colocalization of GP125/CD98 with tropomyosin isoforms at the cell-cell adhesion boundary.

Two monoclonal antibodies designated as 1F6 and 4B10 were obtained on screening for reactivities to CD98-associated molecules by sandwich-type enzyme-linked immunosorbent assaying using hybridoma culture supernatants as the solid phase, cell lysates as an antigen source, and a mixture of biotinylated antibodies to CD98HC as a detector. Flow cytometric analysis with microspheres in combination with 1F6, 4B10, and anti-CD98HC also indicated the association of antibody-defined antigen(s) with CD98. 1F6 and 4B10, stained fibrillate components in fixed and permeated cells but were not reactive with unfixed live cells, suggesting that epitopes reside in the cytoskeleton-associated structure in the intracellular region. Two-color immunostaining followed by confocal microscopy revealed the colocalization of the antigen with CD98 at the cell-cell adhesion boundary of HeLa cells. 1F6 detected proteins with relative molecular masses of 33,000 to 43,000 on immunoblotting analysis involving cell lysates of human and rat cell lines. Analysis with a purified tropomyosin specimen from rabbit skeletal muscle demonstrated that 1F6 and 4B10 recognize tropomyosin. Two-dimensional gel electrophoresis followed by immunoblotting analysis revealed that 1F6 recognizes various tropomyosin isoforms. These results indicated that CD98 physically associates directly or indirectly with tropomyosin, and that this association is closely related to the cell-cell interaction.

Actins↗
PubMed2000

Single-beat estimation of ventricular end-systolic elastance-effective arterial elastance as an index of ventricular mechanoenergetic performance.

BACKGROUND: The ratio of ventricular end-systolic elastance (Ees) to effective arterial elastance (Ea) is known to reflect not only ventricular mechanical performance but also energetic performance. Despite these useful features, technical difficulties associated with estimating Ees make the clinical application of Ees/Ea impractical. We developed a framework to estimate Ees/Ea without measuring ventricular volume or altering the loading condition. METHODS: To achieve this goal, we approximated the ventricular time-varying elastance curve with two straight lines, one for the isovolumic phase and the other for the ejection phase, and characterized the curve with the slope ratio, k, of these two straight lines. Using the concept of the pressure-volume relationship, Ees/Ea is algebraically expressed as Ees/Ea = Pad/Pes (1 + k. ET/PEP) - 1, where Pes is end-systolic pressure, Pad is aortic diastolic pressure, ET is ejection time, and PEP is pre-ejection period. In 11 anesthetized dogs, we recorded arterial and ventricular pressures and ventricular volume and estimated Ees and Ea under various contractile states and loading conditions. RESULTS: An empirical relation between k and Ees/Ea was found as k = 0.53 (Ees/Ea)0.51. Simultaneous solution of these two equations yielded Ees/Ea as a function of Pad/Pes and ET/PEP. The estimated Ees/Ea values correlated well with the measured Ees/Ea values ([Measured Ees/Ea] = 0.96 [Estimated Ees/Ea] + 0.098, r = 0.925, SEE = 0.051). CONCLUSIONS: The proposed framework is capable of estimating Ees/Ea from ventricular and aortic pressure.

Animals↗
PubMed2000

Chronic adriamycin treatment impairs myocardial interstitial neuronal release of norepinephrine and epinephrine.

Although chronic adriamycin (doxorubicin) treatment is known to induce cardiomyopathic heart failure with sympathetic neurohumoral activation in a dose-dependent manner, its effect on local neuronal catecholamine release at the cardiac sympathetic nerve terminals remains to be clearly determined. Using a cardiac microdialysis technique, we measured dialysate norepinephrine (NE) and epinephrine (Epi) concentrations as indices of myocardial interstitial NE and Epi levels. respectively, in rabbits with chronic adriamycin treatment (ADR) (4 mg/kg/week, 6 weeks, n = 8) and in control rabbits (CNT) (n = 6). Exocytotic release was evoked by the local administration of KCl (100 mM) through the dialysis probe. Basal levels of NE and Epi did not differ between the ADR and CNT groups (NE, 11.6 +/- 6.6 vs. 20.4 +/- 17.2 pg/ml; Epi, 4.0 +/- 0.1 vs. 4.6 +/- 1.7 pg/ml: mean +/- SD). The exocytotic release was suppressed in the ADR compared with the CNT group (NE, 191.4 +/- 144.7 vs. 760.5 +/- 337.8 pg/ml; p < 0.05: Epi, 4.2 +/- 0.4 vs. 20.8 +/- 9.9 pg/ml; p < 0.05). We conclude that chronic adriamycin treatment impairs the neuronal exocytotic release of catecholamine at the cardiac sympathetic nerve terminals.

Animals↗
PubMed2000

A novel experimental mouse model of peritoneal dissemination of human gastric cancer cells: different mechanisms in peritoneal dissemination and hematogenous metastasis.

We established a new cell line, AZ-P7a, with high peritoneal-metastatic potential in nude mice. AZ-P7a cells were derived from the human gastric carcinoma line AZ-521, which has low capacity for peritoneal dissemination. AZ-P7a cells developed peritoneal metastasis in 11 / 14 (78.6%) mice, whereas the parental AZ-521 cells developed metastasis in 2 / 6 (33.3%) mice. The metastatic foci in the peritoneum showed essentially the same histological appearance as those induced by parental cells. The tumorigenicity and the motile activity of AZ-P7a cells were stronger than those of the parental AZ-521 cells; in contrast, adhesion to the extracellular matrix and the production of vascular endothelial growth factor by AZ-P7a cells were decreased. In fluorescence-activated cell sorter (FACS) analysis, AZ-P7a cells expressed significantly greater levels of integrins alpha2, alpha3, alpha5, alpha6 and alphavbeta5, as compared with AZ-521 cells. However, alpha1, alpha4, alphavbeta3, hCD44H, hCD44v3, hCD44v6 and hCD44v10 were not expressed in either cell line. AZ-P7a cells developed no liver metastasis when administered by the intrasplenic injection method, though the highly liver metastatic cell line AZ-H5c showed the same rate of peritoneal dissemination as that exhibited by AZ-P7a cells after intraabdominal injection. These findings suggested that the mechanism of peritoneal dissemination differed from that of hematogenous metastasis. Moreover, the latter appears to be controlled by more complex mechanisms than the former. Thus, this cell line might be useful for investigating the mechanism of peritoneal dissemination of human gastric cancer.

Adenocarcinoma↗
PubMed2000

A novel servo-control system that imposes desired aortic input impedance on in situ rat heart.

To clarify the pathophysiological role of dynamic arterial properties in cardiovascular diseases, we attempted to develop a new control system that imposes desired aortic impedance on in situ rat left ventricle. In 38 anesthetized open-chest rats, ascending aortic pressure and flow waveforms were continuously sampled (1,000 Hz). Desired flow waveforms were calculated from measured aortic pressure waveforms and target impedance. To minimize the difference between measured and desired aortic flow waveforms, the computer generated commands to the servo-pump, connected to a side branch of the aorta. By iterating the process, we could successfully control aortic impedance in such a way as to manipulate compliance and characteristic impedance between 60 and 160% of their respective native values. The error between desired and measured aortic flow waveforms was 70 +/- 34 microl/s (root mean square; 4.4 +/- 1.4% of peak flow), indicating reasonable accuracy in controlling aortic impedance. This system enables us to examine the importance of dynamic arterial properties independently of other hemodynamic and neurohumoral factors in physiological and clinical settings.

Algorithms↗
PubMed2000

Counteraction of aortic baroreflex to carotid sinus baroreflex in a neck suction model.

Although neck suction has been widely used in the evaluation of carotid sinus baroreflex function in humans, counteraction of the aortic baroreflex tends to complicate any interpretation of observed arterial pressure (AP) response. To determine whether a simple linear model can account for the AP response during neck suction, we developed an animal model of the neck suction procedure in which changes in carotid distension pressure during neck suction were directly imposed on the isolated carotid sinus. In six anesthetized rabbits, a 50-mmHg pressure perturbation on the carotid sinus decreased AP by -27.4+/-4.8 mmHg when the aortic baroreflex was disabled. Enabling the aortic baroreflex significantly attenuated the AP response (-21.5+/-3.8 mmHg, P<0.01). The observed closed-loop gain during simulated neck suction was well predicted by the open-loop gains of the carotid sinus and aortic baroreflexes using the linear model (-0.43+/-0.13 predicted vs. -0.41 +/-0.10 measured). We conclude that the linear model can be used as the first approximation to interpret AP response during neck suction.

Animals↗
PubMed2000

Closed-loop identification of carotid sinus baroreflex transfer characteristics using electrical stimulation.

Although random aortic pressure (AOP) perturbation according to a binary white noise sequence enables us to estimate open-loop dynamic characteristics of the carotid sinus baroreflex under closed-loop conditions, the necessity of arterial catheter implantation limits the applicability of this method in freely moving animal experiments. Thus, we explored a closed-loop system identification method using electrical stimulation. In 6 anesthetized and vagotomized rabbits, we stimulated the aortic depressor nerve with a binary white noise sequence (0-10 Hz) under baroreflex closed-loop conditions while measuring cardiac sympathetic nerve activity (SNA) and AOP. We used a closed-loop identification method to estimate the peripheral arc transfer function from SNA to AOP. The peripheral arc transfer function approximated a second-order low-pass filter and its fitted parameters did not differ from those obtained by an open-loop identification method (dynamic gain: 1.16+/-0.32 vs. 1.02+/-0.11; natural frequency: 0.08+/-0.03 vs. 0.09+/-0.03 Hz; damping ratio: 1.53+/-0.15 vs. 1.57+/-0.21). In 6 different rabbits, we applied intermittent rapid pacing (396 beats/min) under baroreflex closed-loop conditions to estimate the neural arc transfer function from AOP to SNA. The neural arc transfer function approximated a first-order high-pass filter and its fitted parameters did not differ from those obtained by an open-loop identification method (dynamic gain: -1.15+/-0.45 vs. -1.06+/-0.05; corner frequency: 0.12+/-0.05 vs. 0.13+/-0.03 Hz). In conclusion, the closed-loop identification method using electrical stimulation is effective to estimate the neural and peripheral arc transfer functions.

Animals↗
PubMed2000

[Analysis of the contractions evoked by sympathetic nerve stimulation, and thermal effect on the guinea-pig vas deferens--study as a model for the thermotherapy of benign prostatic hyperplasia].

BACKGROUND: The present study was designed to investigate the mechanism of thermotherapy on benign prostatic hyperplasia (BPH), using the guinea-pig vas deferens as a model for BPH. The components of contractions elicited by electrical field stimulation and nicotine were analyzed, and the thermal effect on the vas deferens was examined. METHODS: The vas deferens was dissected, suspended vertically through two silver ring electrodes, and attached to an isometric transducer. The electrical stimulation of 10 constant current pulses (10 mA) with 0.3 msec in duration of 5, 10, and 40 Hz was achieved under air-gap condition. Drugs were added directly to a 5 ml Magnus tube containing Tyrode solution (36 degrees C) gassed with a 95% O2-5% CO2 mixture. The components of contractions evoked by electrical stimulation and nicotine were investigated by tetrodotoxin (TTX), and blocking agents of alpha 1-adrenoceptors and/or purinoceptors. Thermal effect on electrically evoked contractions was examined at incubation temperature of 25 degrees C (control), 43 degrees C, 45 degrees C, 46 degrees C and 47 degrees C for 1 hour. RESULTS: Nicotine (200 microM) elicited biphasic contractions, which were triggered by corelease of noradrenaline (NA) and ATP (N-ATP) from sympathetic nerve terminals by activation of prejunctional nicotine receptors. NA and N-ATP caused the corresponding contractions, alpha 1 and N-ATP components, respectively. Combined application of prazosin (1 microM) and suramin (50 microM) abolished these contractions. Activation of post-junctional alpha 1-adrenoceptors by NA caused release of ATP from muscle cells to produce the contraction (alpha 1-ATP component), which was sensitive to both suramin and prazosin. N-ATP and alpha 1 components attributed to fast and slow part of the contraction, respectively. Electrical field stimulation caused biphasic contractions which consisted of both neurogenic (TTX-sensitive) and non-neurogenic (TTX-insensitive) components. An increase in stimulation frequency (5 to 40 Hz) increased the neurogenic components, which contained alpha 1 and N-ATP components, as well as the case of nicotine. The non-neurogenic components consisted of alpha 1-ATP, muscle-derived ATP (m-ATP) and unknown substance 'X' components. Nifedipine (10 microM). L-type Ca2+ channel blocker, markedly reduced the contractions induced by bath applied phenylephrine (alpha 1-agonist, 100 microM) but only partially blocked the contractions produced by bath applied ATP (500 microM). The contractile force in amplitude and neurogenic components induced by electrical field stimulation did not change at 43 degrees C, but both declined significantly above 45 degrees C. The neurogenic components at 45 degrees C and 46 degrees C were suppressed to 22 +/- 6% and 14 +/- 3% (mean +/- SD) of control, respectively. All the contractile responses were abolished at 47 degrees C. CONCLUSION: The contractions of the guinea-pig vas deferens evoked by electrical field stimulation consisted of alpha 1, N-ATP, alpha 1-ATP, m-ATP and X components. Sympathetic nerve fibers in the muscles were completely inactivated by thermal exposure at 47 degrees C for 1 hour. The results suggest that the minimal temperature for thermotherapy of BPH should be 47 degrees C.

Adenosine Triphosphate↗
PubMed2000

Establishment and characterization of a human gastric carcinoma cell line that is highly metastatic to lymph nodes.

The actual mechanisms by which carcinoma cells metastasize to lymph nodes are still unclear, and there is a need to establish in vivo experimental models suitable for the investigation of lymph node metastasis. For the purpose, we established a highly lymph node-metastasizing line, designated AZL5G, derived from a human gastric cancer cell line, AZ521, which had low capacity for lymph node metastasis. AZL5G cells transplanted orthotopically in the nude mouse stomach metastasize predominantly to the regional lymph nodes, showing little potential for hematogenous metastasis. AZL5G tumors developing in the stomach and regional lymph nodes showed poorly differentiated adenocarcinoma with medullary growth, and their histologic appearance strongly resembled that of parental AZ521. The growth activities in vitro of low-metastatic AZ521 and high-metastatic AZL5G were almost the same, but the tumorigenicity in vivo of AZL5G was significantly higher than that of AZ521. AZL5G cells also showed clearly higher abilities of cell locomotion and adhesion to type IV collagen and fibronectin in vitro as compared with AZ521 cells. Flow cytometric analysis demonstrated that the expression of integrin beta1 subfamily except for alpha6 integrin was generally increased in AZL5G cells than in AZ521 cells. Especially, the expression of alpha1 and alpha2 integrins in AZL5G cells was clearly higher than in AZ521, while alpha(v)beta3 integrin, E-cadherin, ICAM-1 and CD44H were not expressed by either cell line. The cell adhesion blocking assay showed that DGEA-containing peptide, which is composed of alpha2 integrin recognition sequence, significantly reduced the adhesiveness of AZL5G cells to type IV collagen as well as to type I collagen and laminin. Furthermore, the administration of anti-alpha2 integrin mAb or DGEA peptide in AZL5G-transplanted nude mice produced a significant reduction in the number of lymph node metastases. These data suggest that the up-regulation of alpha2 integrin expression by gastric cancer cells may play a critical role in the process of lymph node metastasis through the increased adhesiveness to type IV collagen. In conclusion, we established a gastric cancer cell line, AZL5G, with a highly metastatic potential to lymph nodes. This well-characterized line and its in vivo experimental model should be useful for investigation of the mechanisms of lymph node metastasis and for establishment of a new therapeutic approach for human gastric cancer.

Animals↗
PubMed2000

Closed-loop estimation of the open-loop carotid sinus baroreflex transfer function for the use of animal experiments in space.

In order to develop effective counter measures to cardiovascular maladaptation associated with space flight, it is essential to know how dynamic characteristics of blood pressure regulation are altered in space. The open-loop transfer characteristics of the carotid sinus baroreflex can be divided into the neural arc and peripheral arc transfer functions (Ikeda et al. 1996). The neural arc transfer function represents the dynamic input-output characteristics from arterial pressure (AP) to efferent sympathetic nerve activity (SNA), while the peripheral arc transfer function represents those from SNA to AP. Although AP perturbation according to a white noise sequence can be used to estimate the transfer functions under baroreflex closed-loop conditions (Kwanda et al. 1997), arterial catheter implantation necessary to perturb AP limits the applicability of this method to freely moving animal experiments. To overcome this problem, we explored the closed-loop system identification method using electrical stimulation. We used aortic depressor nerve (ADN) stimulation and rapid pacing (RP) of the heart to perturb the arterial baroreflex system.

Algorithms↗
PubMed1999

The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region.

PTEN is a recently identified tumor suppressor inactivated in a variety of cancers such as glioblastoma and endometrial and prostate carcinoma. It contains an amino-terminal phosphatase domain and acts as a phosphatidylinositol 3,4,5-trisphosphate phosphatase antagonizing the activity of the phosphatidylinositol 3-OH kinase. PTEN also contains a carboxyl-terminal domain, and we addressed the role of this region that, analogous to the amino-terminal phosphatase domain, is the target of many mutations identified in tumors. Expression of carboxyl-terminal mutants in PTEN-deficient glioblastoma cells permitted the anchorage-independent growth of the cells that otherwise was suppressed by wild-type PTEN. The stability of these mutants in cells was reduced because of rapid degradation. Although the carboxyl-terminal region contains regulatory PEST sequences and a PDZ-binding motif, these specific elements were dispensable for the tumor-suppressor function. The study of carboxyl-terminal point mutations affecting the stability of PTEN revealed that these were located in strongly predicted beta-strands. Surprisingly, the phosphatase activity of these mutants was affected in correlation with the degree of disruption of these structural elements. We conclude that the carboxyl-terminal region is essential for regulating PTEN stability and enzymatic activity and that mutations in this region are responsible for the reversion of the tumor-suppressor phenotype. We also propose that the molecular conformational changes induced by these mutations constitute the mechanism for PTEN inactivation.

Amino Acid Sequence↗
PubMed1999

Novel therapeutic strategy against central baroreflex failure: a bionic baroreflex system.

BACKGROUND: Central baroreflex failure in Shy-Drager syndrome and traumatic spinal cord injuries results in severe orthostatic hypotension and often confines the patient to the bed. We proposed a novel therapeutic strategy against central baroreflex failure: implementation of an artificial feedback control system able automatically to regulate sympathetic vasomotor tone, that is, a bionic baroreflex system (BBS). With the use of a rat model of central baroreflex failure, we developed the BBS and tested its efficacy. METHODS AND RESULTS: Our prototype BBS for the rat consisted of a pressure sensor placed into the aortic arch, stimulation electrodes implanted into the greater splanchnic nerve, and a computer-driven neural stimulator. By a white noise approach for system identification, we first estimated the dynamic properties underlying the normal baroreflex control of systemic arterial pressure (SAP) and then determined how the BBS computer should operate in real time as the artificial vasomotor center to mimic the dynamic properties of the native baroreflex. The open-loop transfer function of the artificial vasomotor center was identified as a high-pass filter with a corner frequency of 0.1 Hz. We evaluated the performance of the BBS in response to rapid-progressive hypotension secondary to sudden sympathetic withdrawal evoked by the local imposition of a pressure step on carotid sinus baroreceptors in 16 anesthetized rats. Without the BBS, SAP rapidly fell by 49+/-8 mm Hg in 10 seconds. With the BBS placed on-line with real-time execution, the SAP fall was suppressed by 22+/-6 mm Hg at the nadir and by 16+/-5 mm Hg at the plateau. These effects were statistically indistinguishable from those of the native baroreflex system. CONCLUSIONS: These results suggest the feasibility of a BBS approach for central baroreflex failure.

Animals↗
PubMed1999

Development of a servo-controller of heart rate using a cycle ergometer.

In exercise training, precise control of exercise intensity would maximize the training efficacy while minimizing risks. To adjust work rate, heart rate (HR) has been used as a measure of exercise intensity. Thus, we developed a servo-controller of HR using a cycle ergometer. After estimating the transfer function from work rate to HR, we optimized feedback parameters for achieving a quick and stable HR response by means of a computer simulation. We then examined the performance of the servo-controller of HR in 55 healthy volunteers. We set the target HR at 60% and 75% of the age-predicted maximum HR. Times required for HR to reach 90% of the target HR were 136 +/- 33 and 137 +/-22s in the respective protocols. Standard deviations of the steady-state difference between the target and measured HRs were 2.5 +/- 0.6 and 3.8 +/- 1.1 beats/min. We conclude that the developed servo-controller makes it possible to precisely regulate HR and, thereby, exercise intensity.

Adult↗
PubMed1999

Establishment and characterization of human pancreatic carcinoma lines with a high metastatic potential in the liver of nude mice.

To investigate of human pancreatic cancer metastasis to the liver, a pancreatic carcinoma line, HPC-3, was injected into the spleens of nude mice. The cells from a few liver metastatic foci of the mice injected with HPC-3 were expanded in vitro and subsequently injected into the spleens of nude mice. By repeating these procedures, we were able to obtain a cell line, designated HPC-3H4. The mice were observed to have liver metastasis in 6 of 6 (100%) cases injected with HPC-3H4, whereas the rate was 0% at 3 weeks after the intrasplenic injection of HPC-3. The tumorigenicity of HPC-3H4 was more rapid than that of HPC-3. The motile activity of HPC-3H4 was also stronger than that of HPC-3, and the adhesion to the extracellular matrix of HPC-3H4 was stronger than that of HPC-3. We also analyzed the cell surface expression of the metastasis-related adhesion molecules. As a result, no substantial changes were observed in the expression level of adhesion molecules. These results suggest that HPC-3H4 is useful for studies aimed at the prevention of liver metastasis.

Animals↗
PubMed1999

Pharmacokinetic analysis and antitumor efficacy of MKT-077, a novel antitumor agent.

MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4- oxothiazolidin-2-ylidenemethyl] pyridinium chloride), a novel rhodacyanine dye in phase I/II clinical trials, may provide a new approach to cancer therapy based on the accumulation in the mitochondria of the cells of certain carcinomas, for example, those of the colon, breast and pancreas. To support the development of MKT-077 for clinical application as an intravenous (i.v.) therapy, we investigated the metabolic fate of [14C]MKT-077 in BDF1 mice as well as the distribution of MKT-077 in experimental LS174T tumor-bearing mice using a high-performance liquid chromatography (HPLC) method. The plasma levels of 14C after i.v. administration of [14C]MKT-077 declined in a triphasic manner. In the first distribution phase, the levels of 14C decreased with a T1/2 of approximately 5 min. In the second and terminal phase, the T1/2 of 14C was 2.8-4.6 h and 16.2 h, respectively. Cmax (1 min after injection) increased from 0.3 to 1.5 microg/ml linearly, but less than proportionately between the doses. The AUC(0-infinity) at 0.3, 1 and 3 mg/kg were 0.030 +/- 0.002, 0.60 +/- 0.12 and 1.73 +/- 0.25 microg x h/ml, respectively. Plasma clearance was approximately 1.8 l/h per kg (at doses of 1 and 3 mg/kg). The steady state volume of distribution (6.8 and 25.1 l/kg) indicated that MKT-077 distributed as a lipid-soluble molecule. The mean residence time (MRT) was 4.1 (at a dose of 1 mg/kg) and 14.1 h (at a dose of 3 mg/kg). In the first rapid phase (5 min after dosing), 14C radioactivity was detected in most of the tissues and organs, most strongly in the kidney cortex, and not in the central nervous system and testes. In the terminal phase (24 h after dosing), 14C contents increased in the intestinal tract, and in the kidney and liver were nearly to the background level. After i.v. bolus administration at a dose of 3 mg/kg of [14C]MKT-077, the predominant route of elimination of the radioactivity was via the feces, and recoveries of total radioactivity in urine and feces corresponded to 33.5% and 61.1%, respectively. More than 60% was recovered within 24 h and 95% within 1 week. MKT-077 was primarily excreted in unmetabolized form with five unidentified metabolites found in the urine and plasma. Intact MKT-077 was retained in the tumor tissue longer than in plasma and kidney in LS174T tumor-bearing mice receiving MKT-077 at an i.v. therapeutic dose (10 mg/kg). This accumulation decreased very slowly, suggesting that the high membrane potentials of tumor cell mitochondria may help retain the drug in tumors.

Animals↗
PubMed1999

Uncoupling between left ventricular contractility and relaxation after direct-current counter shocks.

Left ventricular (LV) contractility and relaxation are physiologically coupled on the basis of intracellular calcium cycling. The relation has been reported to be unique. However, this may not be always true if relaxation is predominantly impaired. Direct current counter (DC) shocks develop myocardial interstitial edema, inducing diastolic heart failure. Thus, we hypothesized that LV contractility-relaxation coupling would be altered in an experimental model of diastolic dysfunction by DC shocks. The relation between Emax (LV contractility index) and the time constant of LV pressure decay (tau) was evaluated in isovolumic contraction of seven isolated, blood perfused dog hearts. There existed a hyperbolic relation between Emax and tau in control (= pre-DC) hearts. After the application of five consecutive 80 J DC shocks, Emax was unchanged (from 4.6 +/- 1.0 to 5.2 +/- 0.8 mmHg x ml(-1) x 100 g) but tau was markedly prolonged (from 36 +/- 12 to 74 +/- 38 ms, P < 0.01). Thus, DC shocks induced a strikingly upward displacement of the hyperbolic curve compared with the control. The slope of the linear relation between Emax and the reciprocal of tau (= a relaxation velocity index normalized for contractility) significantly decreased after DC shocks. We conclude that the coupling between LV contractility and relaxation is not unique, but can be altered acutely by DC shocks. A dissociation of contractility-relaxation coupling may be of help for distinguishing diastolic heart failure and exploring its pathogenesis.

Animals↗
PubMed1999

Determination of MKT-077, a novel antineoplastic agent, in plasma samples by high-performance liquid chromatography and its application to pharmacokinetics in rats.

A simple high-performance liquid chromatographic method was developed for determination of a novel antineoplastic agent MKT-077 in plasma. MKT-077 was extracted from 50 microl of plasma with acetonitrile containing 1 ml trifluoroacetic acid per liter. Chromatographic separation was achieved within 13.5 min using a reverse-phase Puresil C18 analytical column. A visible detector operated at 490 nm was used. The linearity of the calibration curve was obtained (r2 = 0.99986) over the analytical range of 10-500 ng/ml(-1). The intra- and inter-assay precision was in the range of 0.9-11.1 and 0.3-4.4%, respectively. The intra- and inter-assay bias ranged from -7.3 to 11.1% and from 0.4 to 11.6%, respectively. The utility of this assay was demonstrated after the administration of a single dose of MKT-077 to rats. The plasma elimination half-life of MKT-077 was 1.8-4 h.

Animals↗