Biomedical subjects

S Mohri

Publications and source records attributed to S Mohri.

At least 37 records · Page 2Linked to original sources

PubMed1999

Total Ca handling in canine mild Ca overload failing heart.

We analyzed total Ca handling of the left ventricle (LV) in the mildly failing heart preparation induced by a temporary intracoronary Ca overloading intervention in eight excised and cross-circulated canine hearts. This Ca intervention consisted of interruption of coronary blood perfusion by Ca-free oxygenated Tyrode perfusion for 10 min followed by high-Ca (16mmol/l) oxygenated Tyrode perfusion for 5 min. This intervention decreased the LV contractility index, Emax (end-systolic maximum elastance), by 40% after restoration of the blood cross-circulation. We expected a Ca overload or paradox failing heart resembling the postischemic stunned heart and being characterized by an increased O2 cost of Emax. However, LV O2 consumption under mechanically unloading conditions decreased by 30% from control without increasing the O2 cost of Emax. To obtain a mechanistic view of this failing heart, we investigated cardiac total Ca handling by our integrative analysis method. In this method, we obtained the internal Ca recirculation fraction (RF) from the decay beat constant of the postextrasystolic potentiation following each sporadic spontaneous extrasystole in these failing LVs. We combined the RF with the decreased Emax and the unchanged O2 cost of Emax in our recently developed formula of total Ca handling. We found that these failing LVs had a slightly but significantly increased RF accompanied by either a slightly increased futile Ca cycling or a slightly decreased Ca reactivity of Emax, or both. Any of these three possible changes can account for the unchanged O2 cost of Emax. This result indicates that the present mildly failing heart has not yet fallen into a typical Ca overload or paradox by the temporary Ca overloading intervention.

Animals↗

PubMed1999

Myocardial mechanical restitution and potentiation partly underlie alternans decay of postextrasystolic potentiation: simulation.

We have reported that the postextrasystolic potentiation (PESP) decays in alternans or monotonically, respectively, depending on whether the first postextrasystolic beat interval has a compensatory pause or not, in the canine left ventricle. To get better mechanistic insight into the alternans PESP decay, we hypothesized that the myocardial mechanical restitution and potentiation could partly account for both types of PESP decay. To test this hypothesis, we simulated PESP decay on a computer using a documented equation combining myocardial mechanical restitution and potentiation. We changed the first postextrasystolic beat interval after a fixed extrasystolic beat interval without changing regular and other postextrasystolic beat intervals. The simulated PESP decayed in alternans or monotonically as a function only of the first postextrasystolic beat interval. Thus, the myocardial mechanical restitution and potentiation could partly account for both alternans and monotonic decay of PESP. We conclude that myocardial mechanical restitution and potentiation may partly underlie the initial two alternating beats, the first beat being the most potentiated and the second beat being the most depressed, of alternans PESP decay in the canine heart.

Animals↗

PubMed1999

The laminin-derived peptide YIGSR (Tyr-Ile-Gly-Ser-Arg) inhibits human pre-B leukaemic cell growth and dissemination to organs in SCID mice.

The YIGSR (Tyr-Ile-Gly-Ser-Arg) laminin beta1 chain sequence has an inhibitory effect on tumour growth and the metastasis of melanoma and fibrosarcoma cells. In the present study, we investigated whether the multimeric YIGSR peptide (Ac-Y16) has an antiproliferative effect and/or prevents the metastasis of human pre-B acute lymphoblastic leukaemia cells (NALM6) in severe combined immune deficient (SCID) mice. In in vitro studies, Ac-Y16 significantly inhibited leukaemic cell colony formation and the invasion of NALM6 cells in a Matrigel-based assay. The tumour growth and leukaemic infiltration in peripheral tissues were also analysed in SCID mice 9 weeks after NALM6, Matrigel and Ac-Y16 were subcutaneously co-injected. The weight of the subcutaneous tumours was significantly suppressed by Ac-Y16 in a dose-dependent manner. Flow cytometry analysis showed that the leukaemic infiltration was significantly inhibited in all organs with 1.5-2.0 mg of Ac-Y16. Leukaemic infiltrations in the brain were inhibited with 0.5 mg of Ac-Y16, and those in brain and bone marrow were also inhibited with 1.0 mg of Ac-Y16. With Ac-S16, a control-scrambled peptide, the only significant inhibition of the leukaemic infiltration was observed in bone marrow at a much higher dose. These data suggest that the multimeric YIGSR peptide can inhibit the tumour growth and metastasis of leukaemic cells and may be useful as a potential therapeutic reagent for leukaemic infiltrations.

Actins↗

PubMed1999

Brain injury does not modify transmissible spongiform encephalopathy caused by intraperitoneal inoculation with Fukuoka-1 strain.

The pathogenesis of neuroinvasion in Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies following the peripheral uptake of a disease agent is still not fully understood. The possibility of neuroinvasion either being established or being accelerated by an insult to the brain has not previously been tested. The experiment described herein was designed to examine this possibility by wounding the brain following an intraperitoneal challenge with a mouse-adapted strain of human transmissible spongiform encephalopathy, Fukuoka-1 strain. The results showed that brain injury introduced in any period before the appearance of cerebral abnormal prion protein deposition modified neither the clinical features, including the incubation period, nor the histopathology of the mice. Our findings suggest that neurovirulence of the agent may not be sufficiently promoted by brain injury.

Animals↗

PubMed1999

A chicken monoclonal antibody with specificity for the N-terminal of human prion protein.

Chickens were immunized with human prion protein (PrP) peptide H25 (amino acid residues 25-49) coupled to keyhole limpet hemocyanin. From a fusion experiment using the chicken fusion partner cell line MuH1 and immune spleen cells, one mAb, HUC2-13, was generated which reacted with the peptide. HUC2-13 was specific for a pentapeptide (RPKPG) of the N-terminal of the peptide H25. In Western blotting analysis, the mAb reacted with PrP materials from a human Creutzfeldt-Jakob disease (CJD) case and the membrane fraction from normal murine brain, but not with the same materials pretreated with proteinase K. When compared with the HUC2-13 and the conventional mouse mAb 3F4, the background stainings using the HUC2-13 were minimal. In immunohistochemistry, the HUC2-13 stained positively with kuru plaques in brain sections from patients with Gerstmann-Straussler syndrome (GSS), and also reacted with synaptic structures of the CJD patients. However, any immunolabelings using the HUC2-13 were not observed in the section from a patient with amyotrophic lateral sclerosis (ALS) as CJD-negative control. These results indicate that the mAb HUC2-13 is a suitable tool for immunological and diagnostic analyses of prion disease in humans and other mammals.

Amino Acid Sequence↗

PubMed1999

O(2) cost of contractility but not of mechanical energy increases with temperature in canine left ventricle.

We investigated the effects of myocardial temperature on left ventricular (LV) mechanoenergetics in the excised, cross-circulated canine heart. We used the framework of the LV contractility (E(max))-pressure-volume area (PVA; a measure of total mechanical energy)-myocardial oxygen consumption (VO(2)) relationship. We have shown this framework to be useful to integrative analysis of the mechanoenergetics of a beating heart. In isovolumic contractions at a constant pacing rate, increasing myocardial temperature from 30 to 40 degrees C depressed E(max) and increased the oxygen cost of E(max), which was enhanced by dobutamine, in a linear manner. However, the slope of the VO(2)-PVA relation (reciprocal of contractile efficiency) and its VO(2) intercept remained constant. Q(10) values of E(max), the oxygen cost of E(max), and the oxygen cost of PVA were 0.4, 2.1 and 1.0, respectively, around normothermia. We conclude that the temperature-dependent processes of cross-bridge cycling and Ca(2+) handling integratively depress E(max) and augment its oxygen cost without affecting the oxygen cost of PVA as myocardial temperature increases by 10 degrees C around normothermia.

Animals↗

PubMed1999

Weibull distribution function for cardiac contraction: integrative analysis.

The Weibull distribution is widely used to analyze the cumulative loss of performance, i.e., breakdown, of a complex system in systems engineering. We found for the first time that the difference curve of two Weibull distribution functions almost identically fitted the isovolumically contracting left ventricular (LV) pressure-time curve [P(t)] in all 345 beats (3 beats at each of 5 volumes in 23 canine hearts; r = 0.999953 +/- 0.000027; mean +/- SD). The first derivative of the difference curve also closely fitted the first derivative of the P(t) curve. These results suggest the possibility that the LV isovolumic P(t) curve may be characterized by two counteracting cumulative breakdown systems. Of these, the first breakdown system causes a gradual pressure rise and the second breakdown system causes a gradual pressure fall. This Weibull-function model of the heart seems to give a new systems engineering or integrative physiological view of the logic underlying LV isovolumic pressure generation.

Animals↗

PubMed1999

Suppression of growth and dissemination in human pre-B leukemia cells by tumor necrosis factor-alpha in scid mice.

Tumor necrosis factor (TNF) has been shown to inhibit the growth of ALL cells. Since the systemic administration of TNF for malignancy results in poor response and severe toxicity, future efforts should concentrate on local treatment. Here we examined the suppressive effect of TNF alpha on leukemic cells engrafted in scid mice. NALM6 cells derived from pre-B ALL were injected in scid mice subcutaneously with or without Matrigel. In mice with Matrigel, subcutaneous tumors rapidly increased with time, whereas none of the mice without Matrigel showed any obvious signs of disease or apparent tumors. High levels of leukemic infiltration were observed in peripheral organs in mice with Matrigel by flow cytometry and PCR for human beta-actin mRNA expression, while mice without Matrigel showed low or undetectable infiltration in these organs. Human TNF alpha was also coinjected subcutaneously with NALM6 cells and Matrigel into scid mice. Mice with 10 ng of TNF alpha showed small subcutaneous tumors at 8 weeks, which slowly increased. They were found to have a small number of leukemic cells in peripheral organs by flow cytometry. By PCR, all organs with the exception of lung and brain showed low or undetectable expression of beta-actin. However, a large dose of TNF alpha (100 ng) had no suppressive effect on tumor growth and leukemic infiltration in mouse organs. Similar results were obtained in colony formation of leukemic cells in vitro. To examine the mechanism of the suppressive effect of TNF alpha, the expression of TNF receptors in tumor cells was analyzed by flow cytometry. Parental NALM6 expressed both TNF alpha receptors I (TNFR60) and II (TNFR80), but these expressions were suppressed in tumor cells from mice with Matrigel. Only TNFR80 expression was induced in tumor cells of mice with 10 ng of TNF alpha. The induction of Fas expression was also detected, whereas neither DNA fragmentation nor apoptotic change in histology was observed in tumor cells of mice with TNF alpha. These results suggest that the suppressive effect of TNF alpha on the growth of leukemic cells in scid mice is mediated through the activation of TNFR80 without apoptotic signal.

Animals↗

PubMed1998

A novel neuropeptide, Hym-176, induces contraction of the ectodermal muscle in Hydra.

During the course of a systematic non-targeting screening of peptide signal molecules in Hydra, we identified a novel myoactive neuropeptide called Hym-176. The primary structure of Hym-176 was determined to be APFIFPGPKVamide. It specifically and reversibly induced contraction of the ectodermal muscle of the hydra body column in vivo. However, it had no effect on the ectodermal muscle of the tentacles. The structure-activity relationship analysis showed that the sequence of FIFPGPKVamide is a minimal requirement for the myoactivity. Removal of an amide group from the C-terminus completely abolished the activity. By using the antibody specific to Hym-176, the tissue localization of the peptide in hydra was determined immunohistochemically. The intense immunoreactivity was found in the peduncle nerve cells, indicating that Hym-176 is a neuropeptide.

Amino Acid Sequence↗

PubMed1998

Ventricular pressure-volume area (PVA) accounts for cardiac energy consumption of work production and absorption.

We briefly review that ventricular systolic pressure-volume area (PVA) can predict changes in myocardial O2 consumption (VO2) associated with cardiac work production (positive work) and absorption (negative work). PVA represents the total mechanical energy of cardiac contraction as it is an integral of mechanical energy generated during systole in the cardiac chamber. We have shown that PVA linearly correlates with VO2 under varied pre- and afterload conditions in the left ventricle of the excised cross-circulated canine heart preparation as well as other heart preparations of different species. PVA is the sum of external mechanical work (EW) and mechanical potential energy (PE) which is almost fully convertible to mechanical work without affecting VO2. To compare the energetic effects of cardiac work production and absorption, we varied the timing of the servo pump motion relative to left ventricular (LV) contraction. When the pump fills the LV during diastole and sucks (allows ejection) during systole, cardiac work is produced by the heart, and hence EW > 0. When the pump fills the LV during systole and sucks during diastole, work is absorbed by the heart, and hence EW < 0. The pressure-volume loop rotates counterclockwise when EW > 0. It rotates clockwise when EW < 0. As the result, PVA (= PE + EW) > PE when EW > 0; PVA < PE when EW < 0. We found that VO2 always linearly correlated with PVA regardless of the polarity of EW. Therefore, PVA is the unique determinant of VO2 in a cardiac chamber in a stable contractility.

Animals↗

PubMed1998

Ventricular contractility in atrial fibrillation is predictable by mechanical restitution and potentiation.

We recently found that contractility (Emax) of an individual irregularly arrhythmic beat in electrically induced atrial fibrillation (AF) is reasonably predictable from the ratio of the preceding beat interval (RR1) to the beat interval immediately preceding RR1 (RR2) in the canine left ventricle. Moreover, the monotonically increasing relation between Emax and the RR1-to-RR2 ratio (RR1/RR2) passed through or by the mean arrhythmic beat Emax as well as the regular beat Emax at RR1/RR2 = 1. We hypothesized that this Emax-RR1/RR2 relation during irregular arrhythmia could be attributed to the basic characteristics of the mechanical restitution and potentiation. To test this, we adopted a known comprehensive equation describing the force restitution and potentiation as a function of two preceding beat intervals and simulated contractilities of irregular arrhythmic beats with randomized beat intervals on a computer. The simulated Emax-RR1/RR2 relation reasonably resembled the one that we recently observed experimentally, supporting our hypothesis. We therefore conclude that the primary mechanism underlying the varying contractilities of irregular beats in AF is mechanical restitution and potentiation.

Animals↗

PubMed1998

A new integrative method to quantify total Ca2+ handling and futile Ca2+ cycling in failing hearts.

Ca2+ handling in excitation-contraction coupling requires considerable O2 consumption (VO2) in cardiac contraction. We have developed an integrative method to quantify total Ca2+ handling in normal hearts. However, its direct application to failing hearts, where futile Ca2+ cycling via the Ca2+-leaky sarcoplasmic reticulum (SR) required an increased Ca2+ handling VO2, was not legitimate. To quantify total Ca2+ handling even in such failing hearts, we combined futile Ca2+ cycling with Ca2+ handling VO2 and the internal Ca2+ recirculation fraction via the SR. We applied this method to the canine heart mechanoenergetics before and after intracoronary ryanodine at nanomolar concentrations. We found that total Ca2+ handling per beat was halved after the ryanodine treatment from approximately 60 micromol/kg left ventricle before ryanodine. We also found that futile Ca2+ cycling via the SR increased to >1 cycle/beat after ryanodine from presumably zero before ryanodine. These results support the applicability of the present method to the failing hearts with futile Ca2+ cycling via the SR.

Animals↗

PubMed1998

Effects of Ca2+ and epinephrine on Ca2+ recirculation fraction and total Ca2+ handling in canine left ventricles.

We investigated the effects of intracoronary Ca2+ and epinephrine on the intracellular Ca2+ recirculation fraction (RF) and total Ca2+ handling in the left ventricle (LV) of the excised cross-circulated canine heart preparation. We analyzed LV postextrasystolic potentiation (PESP) following a spontaneous extrasystole that occurred sporadically under constant atrial pacing. All PESPs decayed in alternans and none decayed monotonically. We extracted an exponential decay component from the alternans PESP, determined its beat constant (taue), and calculated RF = exp(-1/taue). Increased intracoronary Ca2+ slightly increased taue and RF, but epinephrine did not change them, although both agents enhanced LV contractility 2-3 times. Neither Ca2+ nor epinephrine affected the sinusoidal decay of the alternans PESP. These results indicate that RF via the sarcoplasmic reticulum was slightly augmented by Ca2+, but not by epinephrine. We combined these RF data with LV Ca2+ handling O2 consumption data and obtained 40-110 micromol/kg as the total amount of Ca2+ handled in one cardiac cycle in the control and enhanced contractile states. These results indicate that this new LV-level approach seems to better the understanding of the Ca2+ mass dynamics responsible for the mechanoenergetics enhanced by inotropic interventions.

Animals↗

PubMed1997

Calcium equally increases the internal calcium recirculation fraction before and after beta-blockade in canine left ventricles.

We studied whether intracoronary Ca administration after beta-blockade would increase the internal Ca recirculation fraction (RF) analogously to the Ca administration before beta-blockade. This was performed in excised cross-circulated canine hearts. We analyzed the exponential decay component of the postextrasystolic potentiation (PESP) following a spontaneous extrasystole. All the PESPs decayed in alternans with atrial pacing at a constant rate. We obtained the time constant (tau(e)) of the monoexponential decay component of the alternans PESP. An increment of intracoronary Ca by 1.5 mmol/l enhanced the left ventricular contractility index Emax (end-systolic maximum elastance) by 2.5 times before and after beta-blockade with propranolol. The intracoronary Ca after beta-blockade slightly but significantly increased tau(e), and hence increased RF calculated from tau(e) by RF = exp(-1/tau(e)). This was analogous to the slightly increased tau(e) and RF with Ca before beta-blockade. We speculate that the myocardial cyclic AMP-dependent phosphorylation level would not significantly alter the effect of intracoronarily administered Ca on myocardial Ca handling, in terms of tau(e) and RF.

Adenosine Monophosphate↗

PubMed1997

Effects of skin metabolism on percutaneous penetration of lipophilic drugs.

Effects of skin metabolism on percutaneous penetration of drugs with high lipophilicity were studied in vitro using rat skin pretreated with and without an esterase inhibitor, diisopropyl phosphorofluoridate [also known as diisopropyl fluorophosphate (DFP)]. Without DFP, about 96% of the total penetrated amount appeared as metabolized p-hydroxybenzoic acid in the receptor fluid after application of butylparaben, whereas about 30% penetrated as intact form after application of propylparaben. On the other hand, metabolized p-hydroxybenzoic acid was not defected in the receptor fluid under pretreatment with DFP. DFP significantly decreased (p < 0.05) the total amount that penetrated after application of butylparaben, but it did not significantly affect that of propylparaben. The results indicate that skin metabolism directly affects total amount that penetrated in the case of highly lipophilic drugs, and it was found that the higher metabolic rate to hydrophilic drugs is, the greater the amount that penetrated the skin would be. Thus, when optimal prodrugs are designed for the purpose of enhancing percutaneous penetration, we propose that the bioconversion rate to parent drugs as well as the lipophilicity of prodrugs becomes an important consideration.

Animals↗

PubMed1996

Effects of an oral adsorbent on cisplatin-induced nephropathy in rats.

A 26-week experiment was designed to determine the effect of an oral adsorbent, AST-120 (Kremezin), in rats with cisplatin-induced interstitial nephropathy. We found that creatinine clearance during the 24th week of the experiment was significantly higher in the AST-120-treated rats (n = 11) than in the control animals (n = 11) (1.09 +/- 0.14, vs. 0.63 +/- 0.12 ml/min; p < 0.05). Furthermore, the kidneys, which were examined morphometrically using a computerized image scan, revealed that the AST-120-treated rats had a significantly lower ratio of the tubular cross-sectional area over the cortex and outer medulla cross-sectional area than the control group (0.26 +/- 0.03 vs. 0.38 +/- 0.02; p < 0.05). An additional experiment was conducted to see if the oral adsorbent affects absorption and excretion of intraperitoneally administered cisplatin. There was no difference between the control group (n = 12) and the AST-120-treated group (n = 12) in serum concentration or urinary excretion of cisplatin during a 72-hour period after the injection. The results of our experiments suggest that the oral absorbent, AST-120, blunts progressive deterioration of renal function and nephron architecture in cisplatin nephropathy.

Administration, Oral↗

PubMed1995

[Relationship between myocardial perfusion state immediately after reperfusion therapy and left ventricular wall motion improvement in patients with acute myocardial infarction].

The relationship between myocardial contrast echocardiography and improvement of the left ventricular wall motion was studied as an indicator of the prognosis of patients with acute myocardial infarction. Ten patients with acute anterior myocardial infarction who demonstrated successful reperfusion (improved to TIMI grade III) and patency of the responsible coronary artery during the chronic stage (one month after the onset) were selected. The contrast study used 2 ml of sonicated iopamidol injected into the left coronary artery. Two-dimensional echocardiograms were taken at the level of papillary muscle on the short axis for recording in VTR. The results of the contrast study were evaluated using a contrast defect score based on the degree and width of the contrast defect. Percent wall motion improvement was measured as an index of improvement of the left ventricular wall motion and CKmax was used for estimating the extent of myocardial necrosis. There was a good correlation between contrast defect score and CKmax (r = 0.853) or % wall motion improvement (r = 0.77). No correlation was found between coronary occlusion time and CKmax nor between coronary occlusion time and % wall motion improvement. The results suggest that if the score is high, recovery of left ventricular wall motion cannot be expected in patients with acute myocardial infarction who demonstrate successful reperfusion. In such cases, myocardial perfusion has not been effectively restored and myocardial necrosis extended over a wide area. If the score is low, recovery of the wall motion can be expected in the chronic stage even though abnormal left ventricular wall motion area is extensive immediately after reperfusion therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Histological changes in bovine endometrium during the estrous cycle.

Endometrial biopsy specimens were obtained from 46 normally cyclic heifers at known stages of their estrous period to show precise characteristic changes. These tissues were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. The following histological changes were observed during the estrous cycle. Metrorrhagia was observed on Days 0 to 1 (estrus = Day 0). Mitoses in glandular epithelium occurred on Day 5. Basal vacuolation in the surface epithelium occurred on Days 5 to 6. Leukocyte invaded the functional layer on Day 7. Stromal mitoses were observed on Days 9 to 12. The results indicate that clincians need to be aware that histological evaluation is important for the diagnosis of endometrial function and that biopsy is useful for this purpose.

Journal Article↗