Biomedical subjects

H Mizoguchi

Publications and source records attributed to H Mizoguchi.

513 records · Page 29Linked to original sources

PubMedDate not supplied

G protein activation by endomorphins in the mouse periaqueductal gray matter.

The midbrain periaqueductal gray matter (PAG) is an important brain region for the coordination of mu-opioid-induced pharmacological actions. The present study was designed to determine whether newly isolated mu-opioid peptide endomorphins can activate G proteins through mu-opioid receptors in the PAG by monitoring the binding to membranes of the non-hydrolyzable analog of GTP, guanosine-5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS). An autoradiographic [(35)S]GTPgammaS binding study showed that both endomorphin-1 and -2 produced similar anatomical distributions of activated G proteins in the mouse midbrain region. In the mouse PAG, endomorphin-1 and -2 at concentrations from 0.001 to 10 microM increased [(35)S]GTPgammaS binding in a concentration-dependent manner and reached a maximal stimulation of 74.6+/-3.8 and 72.3+/-4.0%, respectively, at 10 microM. In contrast, the synthetic selective mu-opioid receptor agonist [D-Ala(2),NHPhe(4), Gly-ol]enkephalin (DAMGO) had a much greater efficacy and produced a 112.6+/-5.1% increase of the maximal stimulation. The receptor specificity of endomorphin-stimulated [(35)S]GTPgammaS binding was verified by coincubating membranes with endomorphins in the presence of specific mu-, delta- or kappa-opioid receptor antagonists. Coincubation with selective mu-opioid receptor antagonists beta-funaltrexamine or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH(2) (CTOP) blocked both endomorphin-1 and-2-stimulated [(35)S]GTPgammaS binding. In contrast, neither delta- nor kappa-opioid receptor antagonist had any effect on the [(35)S]GTPgammaS binding stimulated by either endomorphin-1 or -2. These findings indicate that both endomorphin-1 and -2 increase [(35)S]GTPgammaS binding by selectively stimulating mu-opioid receptors with intrinsic activity less than that of DAMGO and suggest that these new endogenous ligands might be partial agonists for mu-opioid receptors in the mouse PAG.

Analgesics, Opioid↗

PubMedDate not supplied

Myeloblastoma formation in acute myeloid leukemia.

The cell surface markers on the leukemic cells of 76 patients with adult acute myeloid leukemia (AML) have been analyzed by indirect immunofluorescence, and the presence of CD56+ leukemic cells was detected in ten of these patients. Four of these 10 CD56+ AML patients developed extramedullary myeloblastomas and in two of them an intracranial myeloblastoma. In contrast, in the remaining 66 CD56- AML patients, only one patient developed a myeloblastoma formation of the subcutaneous. It may be that the CD56 antigen which is an isoform of the neural cell adhesion molecule (NCAM), expressed on neurons, satellite cells of skeletal muscle cells, and on stromal cells, binds these tissues by a homophilic mechanism. CD56+ leukemic cells are capable of invading and of surviving in extramedullary tissues, where they proliferate and develop into a myeloblastoma. Because of this possibility, CD56+ AML patients should be carefully monitored for signs of myeloblastoma formation.

Adolescent↗

PubMedDate not supplied

Protection by constitutively formed nitric oxide of intestinal damage induced by indomethacin in rats.

In the present study, we investigated a protective role of constitutively occurred nitric oxide (NO) against indomethacin-induced intestinal lesions in rats. Indomethacin (10 mg/kg) was given s.c. to animals without fasting, and the intestinal mucosa was examined for lesions 24 h later. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) was given s.c. 0.5 h before or 6 hr after indomethacin, while the NO donor (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexnamine (NOR-3) was given s.c. 0.5 h before indomethacin. Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility and bacterial translocation. These lesions were markedly prevented or worsened, respectively, by later or prior administration of L-NAME (20 mg/kg), in a L-arginine-sensitive manner. The worsening effect of L-NAME (5-20 mg/kg) on these lesions was dose-dependently observed in association with further enhancement of the bacterial translocation and intestinal hypermotility following indomethacin. By contrast, prior administration of NOR-3 (1-6 mg/kg) dose-dependently prevented the development of intestinal lesions, together with suppression of the bacterial translocation and intestinal hypermotility in response to indomethacin. On the other hand, both indomethacin and L-NAME decreased intestinal mucus and fluid (water) secretion in the small intestine, while NOR-3 increased these secretions. These results suggest that (1) NO occurred constitutively exerts a protective action against indomethacin-induced intestinal ulceration, and (2) this effect is related with prevention of bacterial translocation, the process functionally associated with increase of mucus and fluid secretions as well as inhibition of intestinal hypermotility.

Animals↗

PubMedDate not supplied

Protection by aspirin of indomethacin-induced small intestinal damage in rats: mediation by salicylic acid.

Most of non-steroidal anti-inflammatory drugs (NSAIDs) except aspirin (ASA) produce intestinal damage in rats. In the present study, we re-examined the intestinal toxic effect of ASA in rats, in comparison with various NSAIDs, and investigated why ASA does not cause damage in the small intestine, in relation to its metabolite salicylic acid (SA). Various NSAIDs (indomethacin; 10 mg/kg; flurbiprofen; 20 mg/kg; naproxen; 40 mg/kg; dicrofenac; 40 mg/kg; ASA; 20-200 mg/kg) were administered s.c., and the small intestinal mucosa was examined macroscopically 24 h later. All NSAIDs tested, except ASA, caused hemorrhagic lesions in the small intestine, with a decrease of mucosal PGE(2) contents. ASA did not provoke any damage, despite inhibiting (prostaglandin) PG production, and prevented the occurrence of intestinal lesions induced by indomethacin, in a dose-related manner. This protective action of ASA was mimicked by the equimolar doses of SA (17.8-178 mg/kg). Indomethacin caused intestinal hypermotility, in preceding to the occurrence of lesion, and this event was followed by increases of enterobacterial translocation in the mucosa. Both ASA and SA prevented both the intestinal hypermotility and the bacterial translocation seen after indomethacin treatment. In addition, the protective effect of SA was not significantly influenced by either the adenosine deaminase or the adenosine receptor antagonists. Following administration of ASA, the blood SA levels reached a peak within 30 min and remained elevated for more than 7 h. These results suggest that SA has a cytoprotective action against indomethacin-induced small intestinal lesions, and this action may be associated with inhibition of the intestinal hypermotility and the bacterial translocation, but not mediated by endogenous adenosine. Failure of ASA to induce intestinal damage may be explained, at least partly, by a protective action of SA, the metabolite of ASA.

Adenosine Deaminase↗

PubMedDate not supplied

A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome.

Patients with a myelodysplastic syndrome (MDS) which has a risk of leukaemic change exhibit a variable clinical course. It has been suggested that the development of leukaemia in patients with MDS may be related to chromosomal abnormalities or genetic alterations: somatic mutation of the N-ras gene is now considered to be a critical step in the genetic basis of human leukaemogenesis. Here we report that DNAs of bone-marrow cells from three out of eight patients with MDS contained an activated N-ras oncogene, as detected by an in vivo selection assay in nude mice with transfected NIH 3T3 cells. Molecular analysis revealed the same single nucleotide substitution at codon 13 in all three transforming N-ras genes. Each of the three patients showed a progression of the disease and a resulting leukaemic change within the following year. Our observation of the mutation at codon 13 in leukaemic cell DNAs from all three cases suggests that activation of the N-ras gene is important in the development of leukaemia in some MDS cases.

Amino Acid Sequence↗

PubMedDate not supplied

Sequential renal hemodynamics in experimental benign and malignant hypertension.

To examine the sequential renal hemodynamic changes in experimental renovascular hypertension, the uninephrectomized dog was studied immediately after renal artery constriction, throughout chronic benign hypertension, and during malignant hypertension. Intrarenal resistance fell immediately after renal artery constriction, but rose above control within hours. Intrarenal infusion of teprotide resulted in vasodilatation during the first 3 days but failed to do so during the chronic phase of benign hypertension. During the transition from benign to malignant hypertension, angiotensin II-dependent renal vasoconstriction developed associated with natriuresis, plasma volume contraction and a vicious cycle of hyperreninemia and severe vascular damage.

Angiotensin II↗

PubMedDate not supplied

Imipenem-cilastatin monotherapy in severe infections accompanying hematological malignancies.

Imipenem-cilastatin (imipenem 1 to 4 g/day) was administered to patients with severe infections accompanying granulocytopenia in hematological malignancies. Monotherapy with imipenem-cilastatin was effective in 62.1% of the patients, and also effective even they were severely neutropenic. When imipenem-cilastatin was administered as the first-choice therapy, the efficacy was much better, at 73.3%. Both Gram-positive and Gram-negative infections were curable by the monotherapy with imipenem-cilastatin.

Agranulocytosis↗

PubMedDate not supplied

Intestinal protection by lafutidine, a histamine H(2)-receptor antagonist, against indomethacin-induced damage in rats--role of endogenous nitric oxide.

BACKGROUND: We previously reported that lafutidine ((I)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl] acetamide), a novel histamine H(2)-receptor antagonist, protects the small intestine against indomethacin-induced damage, mediated by capsaicin-sensitive afferent neurons (CSN). MATERIAL AND METHODS: In the present study, we investigated whether or not the protective action of lafutidine against indomethacin-induced intestinal damage is mediated by endogenous nitric oxide (NO). Male SD rats were given indomethacin (10 mg/kg, s.c), killed 24 hr later, and the small intestinal mucosa was examined. Lafutidine (10 mg/kg) and capsaicin (10 mg/kg) was given p.o. twice 0.5 hr before and 9 hr after indomethacin. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME: 10 mg/kg) or the selective iNOS inhibitor aminoguanidine (10 mg/kg) was given s.c. 1 hr before lafutidine, while L-arginine (200 mg/kg) was given i.p. 10 min before L-NAME. RESULTS: Indomethacin produced severe lesions in the small intestine, accompanied by increases in enterobacterial translocation in the mucosa. Both lafutidine and capsaicin significantly reduced the severity of these lesions, together with suppression of bacterial translocation. The protective action of lafutidine as well as capsaicin was almost totally abolished by L-NAME but not aminoguanidine, in a L-arginine-sensitive manner. Both lafutidine and capsaicin significantly increased intestinal mucus secretion, and these effects were also attenuated by prior administration of L-NAME. The exogenous NO donor NOR-3 prevented indomethacin-induced intestinal lesions at the dose that stimulated the mucus secretion and inhibited the bacterial translocation. CONCLUSIONS: These results suggest that lafutidine protects the small intestine against indomethacin-induced damage, the action being dependent on CSN and mediated by endogenous NO produced by cNOS. The protective action of lafutidine may be attributable to suppression of the bacterial translocation following indomethacin, probably due to stimulation of intestinal mucus secretion.

Acetamides↗

PubMedDate not supplied

Intraarterial infusion of cisplatin with and without preoperative concurrent radiation for urinary bladder cancer: a preliminary report.

We evaluated the clinical efficacy of treating urinary bladder cancer by intraarterial infusion of cisplatin using an implanted reservoir with and without preoperative concurrent radiation. No previous reports have compared the results obtained by these two methods of treatment. Twenty-three patients with bladder cancer were treated by intraarterial infusion of cisplatin using an implanted reservoir with (n = 13) and without (n = 10) concurrent radiation. The cisplatin plus radiation group received intraarterial cisplatin at a total dose of 200-400 mg and concurrent radiation to a total dose to 30 Gy. The cisplatin group received intraarterial cisplatin at a total dose of 100-600 mg. In the cisplatin plus radiation group, the overall tumor response rate was 92%. Seven of 13 (53%) patients obtained complete response (CR), and the 2-year actuarial survival rate was 92%. Only one of the seven complete responders has had a local recurrence. In the cisplatin group, the overall tumor response rate was 90%. Four of 10 (40%) patients obtained CR, and median survival was 8 months. Three of the four complete responders have had local recurrence. There was no significant difference between these two groups in the frequency of side effects. Concurrent radiation therapy with intraarterial cisplatin resulted in a very low rate of recurrence of bladder cancer compared with intraarterial cisplatin therapy alone. This method was useful for urinary bladder cancer and may become the treatment of choice for this type of cancer.

Aged↗