Biomedical subjects

M Nishio

Publications and source records attributed to M Nishio.

At least 127 records · Page 7Linked to original sources

PubMed1998

TMC-52A to D, novel cysteine proteinase inhibitors, produced by Gliocladium sp.

New cysteine proteinase inhibitors, TMC-52A, B, C, and D, were isolated from the fungal fermentation broth. On the basis of a taxonomical study, the producing strain, F-2665, was characterized as Gliocladium sp. Spectroscopic analyses and chemical degradation have shown TMC-52A to D to be epoxysuccinyl peptides. TMC-52A to D strongly inhibited cysteine proteinases, in particular, cathepsin L with IC50 values of 13 nM, 10nM, 10nM, and 6nM, respectively.

Cathepsin L↗

PubMed1998

[Clinical evaluation for radiotherapy of metastatic brain tumors in lung cancer: prognostic analyses relevant to QOL].

From 1986 through 1992, 144 patients with metastatic brain tumors of lung cancer were treated with X-ray irradiation to whole brain or a comparatively wide field of the brain. To identify the subset of patients indicated for boost therapy like a stereotactic radiotherapy, we have analyzed the treatment results concerning both survival and performance status (PS). Median survival time of the patients in good PS (0-2) was 6.7 months, which was significantly better than 2.3 months in poor PS (3-4). Complete tumor-resectability, age, steroid therapy and condition within two months after the beginning of brain irradiation, seemed to be important prognostic indicators correlated with PS by both univariate and multivariates analyses.

Adolescent↗

PubMed1998

[A case of traumatic subacute subdural hematoma presenting symptoms arising from cerebral hemispheric edema].

Traumatic subacute subdural hematoma is a condition in which the major symptoms affecting prognosis most appear in the subacute stage after head trauma, while traumatic acute subdural hematoma is treated conservatively when the symptoms are mild. The cause of the major symptoms occurring in the subacute stage is mostly expansion of the subdural hematoma volume. The authors report a case of traumatic subacute subdural hematoma in which the cause of the major symptoms was cerebral hemispheric edema instead of expansion of the subdural hematoma volume. To our knowledge, only one similar case to the present case has been previously reported. A 44-year-old female fell from the stairs on July 21, 1995 and was suffering from headache. On July 23, she was admitted to our hospital because of generalized convulsion. On admission, she was drowsy but showed no convulsion. Head CT showed an acute subdural hematoma on the right side with a slight midline shift and no other abnormalities. She was treated conservatively because of the mildness of the symptoms and two days later became alert with no symptoms. Thereafter she only complained of occasional headache which was controlled with medicine. On August 3, she suddenly fell into coma. Head CT showed severe cerebral hemispheric edema on the right side without change of the subdural hematoma size. Emergency cerebral angiography showed no definitive abnormalities such as occlusion of the arteries or of the venous sinuses. Craniotomy associated with external decompression was performed. The hematoma was composed of red-brown jelly accompanied with some liquid component and had a thin black-brown outer membrane. While removing the hematoma, bleeding from a vein on the cerebral surface around the sylvian fissure was observed and this location was suspected to be the sources of the bleeding point. Postoperatively, she received steroid and barbiturate therapy associated with moderate hypothermia under hyperventilation. She tolerated this treatment well and left the hospital, on September 26, 1995 with only diplopia during downward gaze. Although the mechanisms of the cerebral hemispheric edema occurring in the subacute stage was unclear, a failure in the cerebral venous circulation arising from compression to the bridging veins, which may be hypoplastic, by the subdural hematoma was suspected to have been the cause.

Adult↗

PubMed1998

Blockage by terfenadine of the adenosine triphosphate (ATP)-sensitive K+ current in rabbit ventricular myocytes.

We examined the blocking effects of terfenadine, an antihistaminic agent, on the ATP-sensitive K+ current (IK,ATP) in rabbit ventricular cells. IK,ATP was induced by cromakalim or NaCN. Terfenadine blocked the IK,ATP with an IC50 of 1.7 microM at -10 mV. This blockage was voltage dependent; depolarization induced a stronger blockage. According to the transmembrane electrical field model, terfenadine interacts with the site located 15 to 18% from the cytoplasmic membrane surface. In line with the assumption that the binding site is near the cytoplasmic surface, terfenadine applied to the cytoplasmic solution potently inhibited the single-channel activity for IK,ATP in the inside-out configuration (IC50 0.19 microM). In contrast, terfenadine applied to the external solution did not affect the channel activity in the cell-attached configuration, but inhibited it when applied into the pipette. The inhibition of the single channels by terfenadine was accompanied by flickering of the channels. These findings suggest that 1) terfenadine blocks the ATP-sensitive K+ channel in the open state, 2) the binding site is near the internal membrane surface and 3) terfenadine is poorly diffusible into the lipid biomembrane and accesses the binding site via the hydrophilic pathway. Terfenadine also inhibited the transient outward K+ current, inward rectifier K+ current and E4031-sensitive rectifier K+ current. However, the inhibition of these repolarization currents by terfenadine at 1 microM was not sufficient to prolong the action potential duration significantly. Whereas, terfenadine (1 microM) prolonged the action potential duration which had been shortened by cromakalim. Terfenadine may modify the ischemia-induced arrhythmias by blocking IK,ATP.

Action Potentials↗

PubMed1998

[Autoimmune thrombocytopenia following syngeneic peripheral blood stem cell transplantation].

A 35-year-old man with non-Hodgkin's lymphoma (NHL) (follicular small cleaved, B cell, stage IVB) received double myeloablative chemotherapy with syngeneic peripheral blood stem cell transplantation (PBSCT). Although platelet recovery was delayed until day 29 after the second transplantation, thereafter trilineage hematopoietic reconstitution was achieved. The evaluation after PBSCT did not detect any residual tumor. The patient was in good health until day 138, when his platelet count suddenly began falling; on day 150, it had fallen to 1.5 x 10(4)/microliter, and the patient was re-admitted for treatment. The bone marrow was normocellular with a normal count and megakaryocyte structure. Other examinations, including serological tests and computed tomography of the neck, chest, abdomen, and retroperitoneum, did not indicate a recurrence of NHL or reveal the cause of thrombocytopenia. The patient's platelet-associated IgG (PAIgG) level was at 70.9 ng/10(7) platelets (normal range: 9-25 ng/10(7) platelets); a diagnosis of thrombocytopenia due to an autoimmune mechanism such as idiopathic thrombocytopenic purpura (ITP) was made. Prednisolone therapy increased the platelet count and reduced the PAIgG level. Thrombocytopenia with an ITP-like mechanism rarely occurs more than 100 days after autologous or syngeneic stem cell transplantation, and should be taken into consideration as a late complication of PBSCT.

Adult↗

PubMed1998

In vitro expansion of CD34+/CD41+ cells from human peripheral blood CD34+/CD41- cells: role of cytokines for in vitro proliferation and differentiation of megakaryocytic progenitors.

The aim of this study is to clarify the transitional change of the proliferation and differentiation of human peripheral blood CD34+ cells to megakaryocytic lineage, focusing on its clinical application. We developed a rapid system to purify human peripheral blood CD34+ cells from healthy volunteers, which produced CD34+ cells with a 90% purity. The purified CD34+ cells predominantly consisted of CD41- cells, and the rate of coexpression of CD41 was 0.6% +/- 0.5%. When the purified cells were cultured in liquid phase for 10 days in the presence of recombinant human stem cell factor (rSCF: a ligand for c-kit), interleukin-3 (rIL-3), and thrombopoietin (rTPO: a ligand for Mpl), the number of CD34+/CD41+ cells increased to 19% +/- 7% of total expanded cells on day 4 (4 days of liquid culture) and then gradually decreased to 2.2% +/- 0.6% on day 10. The absolute number of CD34+/CD41+ cells increased and reached a plateau on day 6, and 1.7 +/- 0.6 x 10(5) CD34+/CD41+ cells were produced by 1 x 10(5) CD34+/CD41- day 0 cells. The CD34-/CD41+ cells appeared on day 6, continuously increased in number until day 10, and constituted the main population of expanded cells on day 10, with a value of 38% +/- 18%. On day 10, 19.5 +/- 10.6 x 10(5) of CD34-/CD41+ cells were produced by 1 x 10(5) CD34+/CD41- day 0 cells. The deletion of rTPO from this cytokine combination decreased the number of CD34+/CD41+ and CD34-/CD41+ cells, after days 6 and 8, respectively. Day 0 cells required rIL-3 for promoting colonies containing megakaryocytes, whereas rTPO alone promoted almost no megakaryocytic colonies from day 0 cells. Thus, a combination of IL-3 and SCF expands CD34+/CD41+ cells from CD34+/CD41- cells, and TPO mainly acts to increase CD34-/CD41+ cells. This study suggests that if the expansion of CD34+/CD41+ is performed in vitro, the 6 days' culture of peripheral blood CD34+/CD41- cells with a combination of IL-3 and SCF with TPO provides the most rapid and stable products of CD34+/CD41+ cells for the rapid recovery of platelets in patients with peripheral blood stem cell transplantation.

Adult↗

PubMed1998

[Clinical results of three types of intraocular lenses for small incision surgery].

We implanted three types of intraocular lens (IOL) in 30 eyes each by small-incision surgery. They were: foldable acryl IOL, foldable silicone IOL and polymethylmethacrylate (PMMA) IOL. We evaluated the following items during three years after surgery: visual acuity, astigmatism, glare disability, contrast sensitivity, tilt and decentering of IOL, corneal endothelial population, aqueous flare and aftercataract. Eyes foldable IOLs were more excellent than PMMA IOLs regarding visual acuity, astigmatism and aqueous flare which are indices for the early postoperative period. PMMA and acryl IOLs were more excellent than silicone IOLs regarding decentration of IOL and aftercataract which are indices for the late postoperative period.

Acrylates↗

PubMed1998

HMN-1180, a small molecule inhibitor of neuronal nitric oxide synthase.

A newly synthesized isoquinolinesulfonamide, HMN-1180 (1-(5-isoquinolinylsulfonyl)-7-methylhomopiperazine), was shown to have selective inhibitory action against rat neuronal nitric oxide synthase (nNOS) with a Ki value of 5.4 microM. Kinetic analysis indicated that the inhibition was competitive with respect to L-arginine but not to calmodulin (CaM). However HMN-1180 exhibited no significant influence up to a concentration of 1 mM on activity of endothelial NOS (eNOS) and it was less active toward inducible NOS (iNOS) (IC50 > 100 microM). Moreover, nNOS bound to a HMN-1180-coupled Sepharose column, but eNOS and iNOS did not. These results suggest that inhibition of nNOS activity is due to direct binding of the compound to the L-arginine binding site of the synthase. Several HMN-1180 derivatives were synthesized and analyzed for their inhibitory actions against nNOS, eNOS and iNOS to cast light on its structure-activity relationships. The potency of inhibition proved dependent on the position of methyl group in the homopiperazine molecule. HMN-1180 was also found to inhibit glutamate stimulated NO production generated by nNOS in the human neuroblastoma cell line SK-N-MC, thus indicating that it is useful tool for elucidating the physiological role of nNOS in neuronal function.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1997

Isoform-specific activation and structural diversity of calmodulin kinase I.

We earlier confirmed that there are isoforms of Ca2+/calmodulin (CaM)-dependent protein kinase I (CaM kinase I) (CaM kinase Ibeta1 and Igamma) beside CaM kinase Ialpha by cDNA cloning (Yokokura, H., Terada, O., Naito, Y., and Hidaka, H. (1997) Biochim. Biophys. Acta 1338, 8-12). Here, we demonstrate the existence of an isoform-specific activation mechanism of CaM kinase I and alternative splicing specifically regulating CaM kinase I (CaM kinase Ibeta2) in the central nervous system. To cast light on isoform structure-enzyme activity relationships, CaM kinase Ibeta1, Ibeta2, and Ialpha were expressed separately using a baculovirus/Sf9 cell expression system. The novel CaM kinase Ibeta2 isoform demonstrated similar catalytic activity to those of CaM kinase Ibeta1 and Ialpha. Interestingly, CaM kinase Ibeta1 and Ibeta2 both can activate CaM kinase Ialpha activity via phosphorylation at Thr177. Reverse transcribed-polymerase chain reaction analysis showed that CaM kinase Ibeta2 is dominant in the cerebrum and cerebellum, whereas CaM kinase Ibeta1 is present in peripheral tissues such as liver, heart, lung, kidney, spleen, and testis. CaM kinase Ibeta2 was also detected with an anti-CaM kinase Ibeta2 antibody in PC12 cells. The results indicate that alternative splicing is a means for tissue-specific expression of CaM kinase Ibeta. Thus the Thr177 residue of CaM kinase Ialpha is phosphorylated by not only CaM kinase kinase but also CaM kinase Ibeta for activation of the enzyme.

Amino Acid Sequence↗

PubMed1997

Analysis of long-term treatment of intracranial germinoma.

PURPOSE: To determine an appropriate treatment policy for intracranial germinoma. METHODS AND MATERIALS: From 1976 to 1992, 51 patients with germinoma (18 with pathologically verified germinoma and 33 diagnosed as having germinoma by neuroimagings) were treated by radiation therapy. Various radiation doses and treatment fields were used. RESULTS: The 10-year cause-specific survival rate for pathologically verified and unverified germinoma was 100% and 96%, respectively. Relapses were noted in four patients, three of whom died from the disease. Two of the four patients with a tumor larger than 4 cm in gross diameter experienced relapse. Two relapses occurred in a nonirradiated spinal canal and two occurred in the irradiation area treated by 25 Gy in 10 fractions and 30 Gy in 20 fractions. No relapse was noted in patients in whom the whole ventricle field was determined precisely using three-dimensional treatment planning. Five patients who were followed at an outpatient clinic experienced significant late neurocognitive dysfunction, which set in after radiotherapy. CONCLUSION: After pathological confirmation, 40 Gy whole-ventricle irradiation using precise three-dimensional treatment planning is appropriate as a standard treatment for most intracranial germinoma.

Adolescent↗

PubMed1997

Human immunodeficiency virus type-1 envelope glycoprotein gp120 induces expression of fusion regulatory protein (FRP)-1/CD98 on CD4+ T cells: a possible regulatory mechanism of HIV-induced syncytium formation.

Syncytium formation is one of major cytopathic effects of human immunodeficiency virus (HIV) infection, and requires the interaction of CD4 molecules on uninfected cells with HIV envelope glycoprotein gp120 expressed on HIV-infected cells. Recent evidence suggests chemokine receptors function as fusion cofactors. We have recently found that fusion regulatory protein (FRP)-1/ CD98 is involved in syncytium formation of HIV gp160-expressing U2ME-7 cells and TALL-1 cells persistently infected with HIV. However, resting lymphocytes were found to express no FRP-1 molecule. In this study, we demonstrated that recombinant gp120 (rpg120) has the ability to induce expression of FRP-1 on peripheral blood mononuclear cells (PBMC). Three-color flow cytometric analysis showed that rgp120-induced FRP-1 was expressed selectively on CD4+ T cells in a dose-dependent manner. FRP-1 expression level was maximum 3 days after addition of rgp120. Anti-CD4 and anti-gp120 antibodies blocked rgp120-induced FRP-1 expression. Co-cultivation of PBMC with HIV-1 gp160-expressing HeLa cells also resulted in the increased expression of FRP-1 on T cells. These results suggest that FRP-1 molecules are induced on CD4+ T cells via CD4-gp120 interaction and may play an important role in regulation of HIV-induced syncytium formation.

Antigens, CD↗

PubMed1997

Enhancement of human parainfluenza virus-induced cell fusion by pradimicin, a low molecular weight mannose-binding antibiotic.

Oligosaccharides, especially mannose residues, expressed on the cell surface, are thought to be important for virus-induced membrane fusion. We examined the effect of mannose-binding compounds, pradimicin derivative BMY-28,864 (PRM) and concanavalin A (Con A), on cell fusion of human parainfluenza type 2 virus (hPIV2)-infected HeLa cells. Syncytium formation of hPIV2-infected HeLa cells was suppressed in the presence of Con A. On the other hand, PRM enhanced cell fusion of hPIV2-infected HeLa cells. These effects were blocked by addition of mannose-rich mannan. However, PRM shows little effect on virus growth and the expression of viral glycoproteins on the cell surface in hPIV2-infected HeLa cells. Fluorescein-isothiocyanate-labeled pradimicin and Con A bound to both uninfected and hPIV2-infected mononuclear cells, indicating that these compounds have an affinity to several cellular component(s). In contrast to Con A, PRM had little affinity to the viral glycoproteins. It is inferred from these results that the enhancement of hPIV2-induced cell fusion is probably due to the interaction between PRM and cellular component(s).

Anthracyclines↗

PubMed1997

Protein tyrosine kinase activation provides an early and obligatory signal in anti-FRP-1/CD98/4F2 monoclonal antibody induced cell fusion mediated by HIV gp160.

The mechanism by which anti-fusion regulatory protein-1 (FRP-1) monoclonal antibody (mAb) induced cell fusion was investigated using U2ME-7 cells that are CD4+U937 cells transfected with the HIV gp160 gene. Protein kinase inhibitors (H-7, H-89, herbimycin A and genistein) suppressed cell fusion of Cd+U2ME-7 cells induced by anti-FRP-1 mAb. H-7 and H-89 also inhibited the cell aggregation, but herbimycin A and genistein did not. Intriguingly, only when herbimycin A was added either before or simultaneously with addition of anti-FRP-1 mAb, was cell fusion suppressed, suggesting that tyrosine kinase is related with the initial step of polykaryocyte formation. Anti-FRP-1 mAb induced the rapid tyrosine phosphorylation of multiple cellular proteins. These effects occurred within 1 min and returned to near baseline by 60 min. The rapid tyrosine phosphorylation was suppressed by herbimycin A and genistein. Although it remains to be determined which protein tyrosine kinase(s) is involved in this response, pp130 tyrosine phosphorylation appears to be a specific and early signal transmitted after the interaction of FRP-1 with a specific antibody. pp130 was present in the cytosol fraction and was distinct from pp125FAK, p130CAS, vinculin, and beta 1-integrin. Thus, our study may present evidence for a novel pathway of protein tyrosine kinases that phosphorylate specific, still unknown protein substrates during polykaryocyte formation.

Antibodies, Monoclonal↗

PubMed1997

Radical radiotherapy for medically inoperable non-small cell lung cancer in clinical stage I: a retrospective analysis of 149 patients.

PURPOSE: In order to obtain the standard treatment results of medically inoperable non-small cell lung cancer (NSCLC) in Stage I in the post-CT scan era, a retrospective analysis of patients who were treated by radical radiotherapy was performed. METHODS AND MATERIALS: 149 cases treated between 1980 and 1989 were accumulated from ten large hospitals in Japan. All patients received a total dose of 55-75 Gy (mean 64.7 Gy) with conventional fractionation. For evaluation of treatment results, complete response (CR) rate, median survival period and long-termed survival rates were used. RESULTS: The median survival of the all cases was 27.2 months and the actuarial 3- and 5-year survival rates were 34.2% and 22.2%, respectively. CR was obtained in 57 cases (38%). The CR rate was strongly correlated with the long-term survival (5-year survival rate in CR group: 35.1% compared with PR + NC group: 14.1% (P < 0.0001)). The size of tumor was also of prognostic importance. In 116 patients who died within 5 years after treatment, 66 patients (57%) died of local tumor regrowth. CONCLUSION: Although the medically inoperable NSCLC patients in Stage I should be offered curative radiation therapy, development of some new steps to increase the CR rate and local control rate is urgently needed.

Aged↗

PubMed1997

Chronic splanchnic hemodynamic effects of low-dose transdermal nitroglycerin versus low-dose transdermal nitroglycerin plus spironolactone in patients with cirrhosis.

We studied the hemodynamic changes following a four-week administration of either low-dose transdermal nitroglycerin (a constant release of 5 mg of nitroglycerin/day) (N = 10) or low-dose transdermal nitroglycerin plus spironolactone (100 mg/day) (N = 9) in patients with cirrhosis and portal hypertension. Two patients in the latter group did not undergo repeat measurements after dropping out because of severe headaches or developing ascites during the study. Transdermal nitroglycerin induced a significant reduction in the hepatic venous pressure gradient (HVPG) (-11.7 +/- 14.9%, P < 0.05), which was associated with a significant reduction of cardiac output (-10.5 +/- 7.3%). Nitroglycerin plus spironolactone induced a significant reduction in the HVPG (-18.3 +/- 16.0%, P < 0.05) associated with a significant reduction of cardiac output (-13.8 +/- 5.6%), right atrial pressure (-35.0 +/- 30.0%), mean arterial pressure (-7.5 +/- 6.8%), and plasma volume (-10.2 +/- 7.0%). The difference of the mean HVPG reduction between the groups was insignificant. A decrease in the HVPG greater than 10% was observed in six of 10 patients (60%) and in five of seven patients (71.4%), defined as "responders," at four weeks. The difference in percentage of responders between the groups was insignificant. We found that in some cirrhotic patients, low-dose transdermal nitroglycerin is potentially useful in the treatment of portal hypertension. Spironolactone as an adjunct to low dose transdermal nitroglycerin did not demonstrate therapeutic advantages in the treatment of portal hypertension in cirrhotics. That there were nonresponders indicates that there are variable responses in splanchnic hemodynamics to these drugs.

Administration, Cutaneous↗

PubMed1997

Negative chronotropic actions of endothelin-1 on rabbit sinoatrial node pacemaker cells.

1. The effects of endothelin-1 (ET-1) on sinoatrial (SA) node preparations of the rabbit heart were studied by means of whole-cell clamp techniques. 2. ET-1 at 1 nM slowed the spontaneous beating activity and rendered half of the cells quiescent. At a higher concentration of 10 nM, the slowing and cessation of spontaneous activity were accompanied by hyperpolarization. 3. In voltage-clamp experiments, ET-1 decreased the basal L-type Ca2+ current (Ica(L)) dose-dependently with a half-maximal inhibitory concentration (EC50) of 0.42 nM and maximal inhibitory response (Emax) of 49.5%. The delayed rectifying K+ current (Ik) was also reduced by 33.2 +/- 11.1% at 1 nM. In addition an inwardly rectifying K+ current was activated by ET-1 at higher concentrations (EC50 = 4.8 nM). These ET-1-induced changes in membrane currents were abolished by BQ485 (0.3 microM), a highly selective ETA receptor antagonist. 4. When Ica(L) was inhibited by ET-1 (1 nM), subsequent application of 10 microM ACh showed no additional decrease in Ica(L), suggesting the involvement of cyclic AMP in the effects of ET-1 on Ica(L). In contrast, 1 nM ET-1 further decreased Ica(L) in the presence of 10 microM ACh, suggesting that ET-1 activates some additional mechanism(s) which inhibit Ica(L). The ET-1-induced Ica(L) inhibition was abolished by protein kinase A inhibitory peptide (PKI, 20 microM) or H-89 (5 microM). However, the Ica(L) inhibition was not affected by methylene blue (10 microM), suggesting a minor role for cyclic GMP in the effect of ET-1 under basal conditions. 5. ET-1 failed to inhibit Ica(L) when the pipette contained GDP beta S (200 microM). However, incubation of the 21.5 +/- 9.5%, whereas it abolished the inhibitory effect of ACh on Ica(L). 6. Intracellular perfusion of 8-bromo cyclicAMP (8-Br cyclicAMP, 500 microM) attenuated, but did not abolish the inhibitory effect of ET-1 on Ica(L). This 8-Br cyclicAMP-resistant component (17.5 +/- 14.4%, n = 20) was not affected by combined application of 8-Br cyclicAMP-bromo cyclicGMP (500 microM), ryanodine (1 microM) or phorbol-12-myristate-13-acetate (TPA; 50 nM). 7. In summary, ET-1 exerts negative chronotropic effects on the SA node via ETA-receptors. ET-1 inhibits both ICa(L) and Ik, and increases background K+ current. The inhibition of ICa(L) by ET-1 is mainly due to reduction of the cyclicAMP levels via PTX-sensitive G protein, but some other mechanism(s) also seems to be operative.

Acetylcholine↗

PubMed1997

Dopamine stimulation of cardiac beta-adrenoceptors: the involvement of sympathetic amine transporters and the effect of SKF38393.

1. Mechanisms underlying beta-adrenoceptor stimulation by dopamine were examined on guinea-pig Langendorff-perfused hearts and isolated cells from the right atrium, by using the chronotropic effects and the enhancement of L-type Ca2+ current (ICa,L) in the presence of prazosin as indicators of beta-adrenoceptor stimulation. Dopamine-induced overflow of noradrenaline (NA) concentrations was measured by high-performance liquid chromatography. 2. Dopamine caused positive chronotropic effects with an EC50 of 2.5 microM and induced NA overflow with a similar EC50 (1.3 microM). The chronotropic effect of dopamine was abolished by bisoprolol (1 microM). 3. The effects of dopamine were maintained during prolonged application, whereas the effects of tyramine faded with time. Dopamine (3 microM) restored the chronotropic effects and the NA release suppressed by pretreatment with tyramine, suggesting a de novo synthesis of NA during the exposure to dopamine. 4. Dopamine (3 microM)-induced NA release was not affected by tetrodotoxin, omega-conotoxin, rauwolscine, ICI118551 or sulpiride, but was inhibited by desipramine, a NA uptake inhibitor (IC50 approximately 1 microM). It was also not affected by GBR12909 and bupropion, dopamine uptake inhibitors in the central nervous system. 5. SKF38393, a D1 receptor partial agonist, potently inhibited the 3 microM dopamine-induced release of NA (IC50 approximately 0.1 microM). D1 receptors are not involved in the DA-induced release of NA, since SCH23390 (3 microM), a potent D1 antagonist, inhibited the NA release only slightly, and dihydrexidine (1 microM) and chloro-APB (1 microM), full D1 agonists, caused no significant NA release. 6. SKF38393 inhibited tyramine-induced overflow of NA, and potentiated the field stimulation-induced NA release. SKF38393 and desipramine retarded the decay of the stimulation-induced tachycardia in a similar manner. These results indicate that SKF38393 is a potent monoamine transport inhibitor and a useful tool for the functional evaluation of indirectly-acting sympathomimetic agonists in the heart. In the presence of SKF38393 (10 microM), dopamine at 1 microM showed no chronotropic effect. 7. Voltage clamp experiments with isolated atrial cells revealed that dopamine is a weak partial agonist. The EC50 for ICa,L stimulation by dopamine was high (13 microM). As a result, dopamine at 1 microM did not affect ICa,L. Bisoprolol abolished the stimulation of ICa,L by dopamine (30 microM), and dihydrexidine (1 microM) did not affect ICa,L. 8. It was concluded that the cardiac effects of dopamine at clinically relevant concentrations (< 1 microM) result almost exclusively from the indirect effect of beta adrenoceptor stimulation, involving the release of NA from sympathetic nerve terminals. The roles of the direct stimulation of beta adrenoceptors by dopamine at these concentrations and the stimulation of postjunctional D1 receptors seem negligible. The desipramine- and SKF38393-sensitive monoamine transporter mediates the release of NA.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1997

Effective high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in a patient with the aggressive form of cytophagic histiocytic panniculitis.

A 20-year-old Japanese man developed generalized, subcutaneous, painless nodules, fever, abnormal liver function, serosal effusions, hepatosplenomegaly, lymphadenopathy and anemia. Skin biopsies revealed lobular panniculitis with a morphologically benign histiocytic infiltration and prominent phagocytosis. Atypical T lymphocytes were also present in the skin and liver. The diagnosis given was aggressive cytophagic histiocytic panniculitis (CHP) or aggressive subcutaneous panniculitic T cell lymphoma (SPTCL). He received cyclophosphamide, doxorubicin, and vincristine on day 1, prednisolone on days 1-5, and etoposide on days 1, 3 and 5 (CHOP-E), with the support of granulocyte colony-stimulating factor. This regimen was repeated every 2 weeks and complete clinical remission (CCR) was attained after three cycles of CHOP-E. As the clinical course of aggressive CHP is recurrent and often fatal, he was given high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT), after five cycles of CHOP-E. He has remained in CCR for 12 months after APBSCT. High-dose chemotherapy followed by APBSCT is considered to be one of the most beneficial therapies for patients with aggressive CHP and aggressive phase SPTCL.

Adolescent↗