Biomedical subjects

H Murakami

Publications and source records attributed to H Murakami.

At least 235 records · Page 13Linked to original sources

PubMed1998

Liposteroid (dexamethasone palmitate) therapy for West syndrome: a comparative study with ACTH therapy.

Dexamethasone palmitate (liposteroid) was used for the treatment of West syndrome and compared with adrenocorticotropic hormone (ACTH) therapy. A single intravenous injection of liposteroid (0.25 mg/kg) was administered seven times in 3 months (total dosage = 1.75 mg/kg) to five symptomatic patients with West syndrome, aged 4-11 months. ACTH (0.025 mg/kg/day) was administered intramuscularly for 6 weeks according to the conventional therapy in Japan (total dosage = 0.625 mg/kg) to five symptomatic patients with West syndrome, aged 6-10 months. Nodding spasm and hypsarrhythmia on EEG disappeared in all patients in the liposteroid therapy group within four doses; however, partial seizures and focal spikes on EEG reappeared in three patients 2 months after the end of liposteroid therapy. In the ACTH therapy group, nodding spasm and hypsarrhythmia on EEG similarly disappeared during treatment in all patients, but nodding spasm reappeared 2 months after therapy in two patients and partial seizures reappeared in one patient 3 months after therapy. No notable adverse reactions occurred in the liposteroid group, but transient dysfunction of the thyroid and anterior pituitary gland and increased levels of serum cortisol were experienced in the ACTH group. These results suggest that glucocorticoid incorporated in a lipid emulsion is useful for the treatment of West syndrome.

Adrenocorticotropic Hormone↗

PubMed1998

Effects of the angiotensin converting enzyme inhibitor temocapril on insulin sensitivity and its effects on renal sodium handling and the pressor system in essential hypertensive patients.

The effects of the angiotensin converting enzyme (ACE) inhibitor temocapril on insulin sensitivity and its effects on renal sodium handling and the pressor system were investigated in essential hypertensive patients (EHT). Seven EHT were hospitalized and underwent a 2-h euglycemic hyperinsulinemic glucose clamp before and after 2 weeks' administration of temocapril (4 mg/day). Insulin sensitivity was calculated using the M value from the infusion rate of glucose with hyperinsulinemia using the glucose clamp method. Renal clearances of sodium, lithium, creatinine, and paraaminohippuric acid were used to calculate fractional proximal and distal tubular reabsorption of sodium (FPR(Na), FDR(Na)) and renal plasma flow (RPF) before and during insulin infusion by the glucose clamp method. Temocapril decreased blood pressure and increased M value significantly. Before temocapril treatment, hyperinsulinemia by the glucose clamp induced significant decreases of urinary excretion of sodium (U(Na) V) and fractional excretion of sodium (FENa). After treatment, these decreases were attenuated, and the change of U(Na) V (deltaU(Na) V) with hyperinsulinemia was significantly higher and deltaFENa showed a higher tendency, compared with before the treatment. FPR(Na) showed no change with hyperinsulinemia before treatment, but significantly decreased after treatment. DeltaFPR(Na) was significantly lower after treatment than that before treatment. FDR(Na) showed an increase with hyperinsulinemia, and deltaFDR(Na) was similar between before and after treatment. RPF showed no change with hyperinsulinemia, and no difference was found in deltaRPF between before and after treatment. Plasma norepinephrine level (PNE) and plasma renin activity (PRA) showed increases, whereas plasma aldosterone concentration (PAC) did not change with hyperinsulinemia. There were no significant differences in deltaPNE, deltaPRA, and deltaPAC between before and after treatment. From these results, it is suggested that in EHT 1) temocapril improves insulin resistance, and 2) although temocapril shows no significant influence on the augmentation of pressor systems by hyperinsulinemia, this agent attenuates the sodium-retaining action of hyperinsulinemia, which may be attributable to suppression of insulin-induced sodium reabsorption at the proximal tubules. These effects may lead to additional beneficial effects in the treatment of essential hypertensives with insulin resistance.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Effects of aging on the insulin actions for the glucose metabolism and renal function in normotensives and essential hypertensives.

It has been suggested that hyperinsulinemia compensating insulin resistance in glucose metabolism may be a pathogenic factor in essential hypertension. On the other hand, age-associated increases in the prevalence of glucose intolerance and hypertension are also well established. The aim of this study is to clarify the influence of aging on insulin sensitivity in glucose metabolism and on renal sodium handling under hyperinsulinemia, which may relate to high blood pressure in insulin-resistant subjects. Fifty-two normotensive subjects and 61 patients with essential hypertension were evaluated in this study. The subjects of these groups were divided into young (<40 years old) and middle-elderly (> or = 40 years old): young normotensives (Y-NT, n = 22); middle-elderly normotensives (ME- NT, n = 30); young hypertensives (Y-HT, n = 9); and middle-elderly hypertensives (ME-HT, n = 52). Using the euglycemic hyperinsulinemic glucose clamp, insulin sensitivity was assessed as M value. Just before the start and the termination of the glucose clamp, creatinine clearance (Ccr) and urinary excretion of sodium (UNaV) were measured. In addition, renal plasma flow assessed as para-aminohippuric acid clearance was also measured at the same time in several subjects; 8 Y-NT, 8 ME-NT, 3 Y-HT, and 10 ME-HT. The M value was significantly lower in ME-NT, Y-HT, and ME-HT, compared to Y-NT, although blood sugar and immunoreactive insulin levels were similar in all four groups. In normotensive subjects, there was a significant, negative correlation between age and M value. However, this correlation was not observed in hypertensive patients. UNaV decreased in ME-NT, Y-HT, and ME-HT, but not in Y-NT under hyperinsulinemia by the glucose clamp, whereas Ccr showed no significant change in any group. In all subjects, the change of UNaV (deltaUNaV) correlated significantly and positively with the M value. Renal plasma flow significantly increased under hyperinsulinemia by the glucose clamp in only Y-HT, but not in the other groups. There was a significant, positive correlation between deltaUNaV and the change of renal plasma flow under hyperinsulinemia by the glucose clamp. These results suggested that both the impairments of the insulin sensitivity and insulin-induced vasodilation at the renal artery with aging may partially contribute to age-related elevation of blood pressure through renal sodium retention by compensating hyperinsulinemia. On the other hand, it seems reasonable to assume that these abnormalities, which can contribute to high blood pressure in essential hypertension, already may exist at lower ages in essential hypertensive patients.

Adolescent↗

PubMed1998

Analysis of antigens targeted by circulating IgG and IgA autoantibodies in 50 patients with cicatricial pemphigoid.

In this study we investigated sera from 50 typical cicatricial pemphigoid (CP) patients. By indirect immunofluorescence on 1 M NaCl-split human skin sections, IgG of 17 sera and IgA of 22 sera reacted with the epidermal side of the split, while IgG of two sera reacted with the dermal side. These latter two sera were later confirmed to be anti-epiligrin CP. By immunoblotting of epidermal extracts, IgG of 14 sera reacted with the 230 kD bullous pemphigoid (BP) antigen (BP230). IgG of 15 sera and IgA of 11 sera reacted with the 180 kD BP antigen (BP180). Interestingly, a bacterial fusion protein containing the BP180 NC16a domain was recognized by IgG of 18 sera but not by IgA of any sera. Fusion proteins containing the C-terminal region of BP180 were recognized by IgG of 20 sera, but it was detected by IgA of only two sera. Our results suggest that, although CP sera show very low titers of autoantibodies, a considerable number of sera contain IgG antibodies to BP180 (either NC16a or C-terminal domain), confirming previous studies. In addition, we showed that greater numbers of IgA antibodies react with BP180, seemingly with different types of epitopes from those for IgG antibodies. Because the specificity of IgG antibodies is not very different from those in BP, IgA antibodies may play a specific role for the development of characteristic clinical features in CP. Future studies should elucidate the pathogenic role of the IgA antibodies in CP.

Animals↗

PubMed1998

Response-oriented individualized induction therapy followed by intensive consolidation and maintenance for adult patients with acute lymphoblastic leukemia: the ALL-87 study of the Japan Adult Leukemia Study Group (JALSG).

The Japan Adult Leukemia Study Group conducted the ALL-87 study to determine whether response-oriented induction therapy and intensive consolidation and maintenance/intensification therapies could increase complete remission (CR) rate and survival in adult acute lymphoblastic leukemia (ALL). Of 121 patients registered, 116 were evaluated. Patients' ages ranged from 15 to 72 years (median, 38 years). Induction therapy, which consisted of doxorubicin, vincristine, cyclophosphamide, L-asparaginase and prednisolone, was given in a response-oriented individualized fashion. Patients were randomly allocated either to receive or not, intrathecal chemotherapy on day 8 of the induction therapy. Complete remission (CR) was obtained in 97 (83.6%) patients (90.2%) in patients of less than 50 years of age and 67.6% in patients 50 years of age or older). At a median follow-up period of 65 months, the predicted 6-year overall survival and event free survival (EFS) rates of 116 patients were 23.4 and 20.0%, respectively. Predicted 6-year survival and disease-free survival (DFS) rates of 97 CR patients were 28.2 and 24.5%, respectively. By multivariate analysis, patients under 40 years of age (P = 0.002) or those with a platelet count of more than 100,000/microliters (P = 0.004) were significant favorable prognostic factors for obtaining CR, and days to CR less than 50 (P = 0.003), patients under 50 years of age (P = 0.005) were significant favorable factors for longer DFS. There was no significant difference in CR rates and DFS between the two randomized groups according to the intrathecal chemotherapy on day 8. Response-oriented induction therapy produced a high CR rate, but fairly intensive consolidation and maintenance/intensification chemotherapies resulted in only a marginal effect on DFS in adult ALL. Although age is one of the most important prognostic factors in ALL, the outcome was unsatisfactory even in younger adult patients using chemotherapeutic regimen employed in this study.

Adolescent↗

PubMed1998

Immunolocalization of aromatase in human breast disorders using different antibodies.

Immunolocalization of aromatase can provide important information about the status of intratumoral aromatase of human breast. We have performed immunohistochemistry of aromatase in surgical pathology specimens of human breast disorders using monoclonal and polyclonal antibodies. Both antibodies yielded satisfactory results in immunostaining of aromatase in normal placenta and normal cycling human ovaries. In human breast disorders, immunostaining or aromatase using monoclonal antibodies can only demonstrate immunoreactivity following antigen retrieval. Immunoreactivity can be detected in both carcinoma and stromal cells but nuclear immunoreactivity, which may be represent artefactural changes, can be detected in both normal and neoplastic breasts. Immunostaining using polyclonal antibody revealed aromatase immunoreactivity in cytoplasm of adipocytes, fibroblasts, vascular wall cells and Schwann cells but intense immunoreactivity was detected in adipocytes adjacent to carcinoma invasion in 68/82 carcinoma cases and stromal cells around carcinoma nest in 58/82 cases. Strong aromatase immunoreactivity was detected in 7/69 benign proliferative breast disorder, 5 of which were sclerosing adenosis. Aromatase immunoreactivity was also detected in carcinoma cells in 7/82 cases but aromatase positive carcinoma cells represent less than 5% of tumor cells in all these cases. These results above indicate that polyclonal antibody is considered to be more suitable for aromatase immunohistochemistry in archival materials of breast disorders but further investigations including easy and reproducible scoring system and production of reliable monoclonal antibodies are required to establish aromatase immunohistochemistry as a reliable method of assessing intratumoral aromatase in human breast disorders.

Antibodies, Monoclonal↗

PubMed1998

Cyclin D1 overexpression related to retinoblastoma protein expression as a prognostic marker in human oesophageal squamous cell carcinoma.

The relationship between aberrant expression of cyclin D1 and retinoblastoma (RB) protein and clinicopathological factors was investigated in 80 patients with oesophageal SCC using immunohistochemical analyses. Heterogeneous staining of cancer cell nuclei with antibody to cyclin D1 was found in 31.3% of patients (25 out of 80 patients). Nuclear staining of cancer cells with anti-RB antibody was homogeneous in 10.0% (8 out of 80 patients) and heterogeneous in 58.8% (47 out of 80 patients). Among cases with homogeneous staining for RB protein, 75% (six out of eight patients) exhibited simultaneous positivity for cyclin D1 (P < 0.05). No significant relationship was found between cyclin D1 or RB protein expression and various clinicopathological parameters. The prognosis of patients with cyclin D1-positive tumours was significantly poorer than that of the other patients (P < 0.01). In addition, when patients with cyclin D1-positive and -negative tumours were stratified according to presence or absence of lymph node metastasis and RB status, the cumulative survival rates in the cyclin D1-positive groups were significantly lower for patients without lymph node metastasis (P < 0.01) and for patients whose tumours were positive for RB (P< 0.0001). These findings suggest the possibility that cyclin D1 positivity is a useful prognostic marker related to lymph node metastasis and RB protein expression in human oesophageal SCC, in addition to clinicopathological factors.

Adult↗

PubMed1998

Chemotherapy vs HLA-identical sibling bone marrow transplants for adults with acute lymphoblastic leukemia in first remission.

There is controversy about whether chemotherapy or an HLA-identical sibling bone marrow transplant is better treatment for adults with acute lymphoblastic leukemia (ALL) in first remission. A previous study of patients treated in 1980-1987 showed similar leukemia-free survivals with these approaches. We re-examined this issue in more recently treated patients receiving different chemotherapy. Chemotherapy subjects (n = 76) participated in trial ALL-87 of the Japan Adult Leukemia Study Group (JALSG). Transplant subjects (n = 214) were reported to the International Bone Marrow Transplant Registry (IBMTR). Treatment-related mortality, relapse and leukemia-free survival were compared after adjusting for differences in subject- and disease-related variables and time-to-treatment. Outcomes differed in persons < or = and >30 years of age. Five-year treatment-related mortality in persons < or =30 years was 3% (95% confidence interval, 0-12%) with chemotherapy vs 32% (23-41%; P < 0.0001) with transplants. The difference was greater among persons >30 years, 13% (2-31%) with chemotherapy vs 57% (43-69%; P < 0.0001) with transplants. Five-year relapse probability in persons < or =30 years was 69% (50-84%) with chemotherapy vs 22% (14-32%; P < 0.0001) with transplants. Among persons >30 years, 5-year relapse was 70% (53-85%) with chemotherapy vs 32% (20-45%; P < 0.0001) with transplants. Leukemia-free survival at 5 years was significantly worse with chemotherapy than with transplants in persons < or =30 years (30% (15-48%) vs 53% (44-63%; P = 0.02)) but not in persons >30 years (26% (13-41%) vs 30% (20-41%; P = 0.70)). We concluded that transplants result in more treatment-related deaths but fewer relapses than chemotherapy. Leukemia-free survival is better with transplants than chemotherapy in persons < or =30 years of age but comparable in older persons.

Adolescent↗

PubMed1998

Fulminant, CMV-associated, haemophagocytic syndrome following unrelated bone marrow transplantation.

We report a case of haemophagocytic syndrome (HPS) occurring after allogeneic bone marrow transplantation (BMT) for acute promyelocytic leukaemia (APL) in a patient in fourth complete remission (CR). Anti-cytomegalovirus (CMV) antibody (Ab) was negative in this patient before BMT. BMT was performed from an HLA-identical unrelated donor who was positive for CMV Ab. After bone marrow engraftment and haematological recovery, severe acute graft-versus-host disease (GVHD) developed. This patient was treated with methylprednisolone in addition to cyclosporin A (CsA). Acute GVHD showed partial improvement, but CMV antigenaemia was observed. Despite administration of gancyclovir and immunoglobulin, CMV antigenaemia showed no improvement and HPS developed. As no other infections or malignancies were observed, we suspect that CMV infection was the trigger for development of HPS.

Adult↗

PubMed1998

Identification of homozygous lipoprotein lipase gene mutation in a woman with recurrent aggravation of hypertriglyceridaemia induced by pregnancy.

We herein report a case of a 40-year-old Japanese woman (patient IT) with a history of recurrent aggravation of hypertriglyceridaemia, pancreatitis and miscarriages in three previous pregnancies. However, strict dietary intervention was applied during a fourth pregnancy. As a result, acute pancreatitis was avoided, and the patient gave birth to a healthy infant. In patient IT, the underlying etiology of the recurrent aggravation of hypertriglyceridaemia during pregnancy was a lipoprotein lipase (LPL) gene aberration. She was homozygous for LPL deficiency due to a nonsense mutation (TGG1401 --> TGA/Trp382 --> Stop) in exon 8 of the LPL gene, which resulted in the absence of LPL activity and immunoreactive LPL mass. Our findings indicate that, in LPL deficiency, pregnancy seriously exacerbates hypertriglyceridaemia and increases the risk of acute pancreatitis, which endangers both the mother and fetus. Early diagnosis of LPL deficiency and appropriate management thereof are essential for normal childbirth.

Abortion, Habitual↗

PubMed1998

Human kallikrein gene delivery protects against gentamycin-induced nephrotoxicity in rats.

The tissue kallikrein-kinin system has been shown to play important roles in cardiovascular and renal function. The aim of this study was to investigate potential protective effects of kallikrein gene delivery in gentamycin-induced nephrotoxicity. Rats were injected subcutaneously with gentamycin daily for 10 to 14 days. Adenovirus, Ad.CMV-cHK carrying the human tissue kallikrein gene or Ad.CMV-LacZ carrying the beta-galactosidase gene under the control of the cytomegalovirus promoter, were delivered intravenously on the first day of gentamycin administration. The expression of human tissue kallikrein mRNA was identified in the kidney, aorta, heart and liver and immunoreactive human kallikrein levels were measured in the serum and urine of rats receiving kallikrein gene delivery. Adenovirus-mediated kallikrein gene delivery significantly increased the renal blood flow, glomerular filtration rates, and urine flow while it attenuated renal tubular damage, cellular necrosis, lumenal protein casts and reduced ventricular weight and cardiomyocyte size. Kallikrein gene delivery caused a decrease in blood urea nitrogen levels and increases in urinary kinin and nitrite/nitrate levels. This study shows that kallikrein gene delivery exhibits protection against gentamycin-induced nephrotoxicity, and raises the potential for kallikrein gene therapy to treat drug-induced renal diseases.

Adenoviridae↗

PubMed1998

Increase in glutamine-non-amidated muropeptides in the peptidoglycan of vancomycin-resistant Staphylococcus aureus strain Mu50.

The peptidoglycan compositions of vancomycin-resistant Staphylococcus aureus (VRSA) strain Mu50 (MIC 8 mg/L) and hetero-VRSA strain Mu3 (MIC 3 mg/L) were compared in order to understand the mechanism of vancomycin resistance. As compared with Mu3, the cell wall of Mu50 had increased amounts of glutamine-non-amidated muropeptides and decreased cross-linking of peptidoglycan with a greatly decreased dimer/monomer ratio of muropeptides. In agreement with this observation, the peptidoglycan of Mu50 bound 1.4 times more vancomycin than that of Mu3. The increase in non-amidated muropeptides and the reduced cross-linking of the cell-wall peptidoglycan may contribute to the vancomycin resistance by increasing the consumption of vancomycin by the pre-existing cell wall of Mu50 and reducing the amount of vancomycin reaching the cytoplasmic membrane where the vital targets of the antibiotic are situated.

Amino Acids↗

PubMed1998

Role of nitric oxide in vascular hyper-responsiveness to norepinephrine in hypertensive Dahl rats.

OBJECTIVE: To determine whether the abnormal vascular responses observed in salt-sensitive hypertension are caused by an impairment in vascular nitric oxide function. DESIGN: Isometric tension was measured in aortic rings isolated from Dahl salt-sensitive and salt-resistant rats fed a regular-salt (0.4% NaCl) or a high-salt (8% NaCl) diet, with and without inhibition of endogenous nitric oxide synthesis. METHODS AND RESULTS: Systolic arterial pressure, measured weekly by the tail-cuff method, increased markedly in DS rats with a high-salt diet but did not increase in the other groups. In aortic rings, norepinephrine evoked dose-dependent contractions which were significantly increased in rings from DS rats with a high-salt diet Pretreatment with Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, increased the norepinephrine-induced contraction in all groups and abolished differences in contractile responses between high-salt DS rats and the other groups. Acetylcholine induced endothelium-dependent relaxation, which was significantly depressed in high-salt DS rats. L-NAME attenuated the acetylcholine-induced relaxation in all groups and abolished the difference in relaxation response between high-salt DS rats and the other groups. Sodium nitroprusside-induced relaxation was significantly depressed in high-salt DS rats. CONCLUSIONS: Vascular hypercontractile responses to norepinephrine in DS hypertensive rats can, in part, be explained by an impairment in endothelial nitric oxide production.

Acetylcholine↗

PubMed1998

Evaluation of clinical usefulness of the microplate agglutination test for serological diagnosis of legionella pneumonia.

Recently, a microplate agglutination test (MPAT) was established for the serological diagnosis of legionella pneumonia. To evaluate its usefulness, this study examined antibody titres in 121 serum samples serially obtained from 40 patients with pneumonia, including 17 cases of confirmed legionella pneumonia. Six of the 17 proven cases became serologically positive within 4 weeks of the onset of pneumonia as assayed by MPAT (cut-off value: four-fold rise to > or = 128 in paired sera or > or = 256 in a single serum specimen), whereas the remaining 11 cases were serologically negative despite serial examination. Four proven cases who were treated with corticosteroids in the acute phase had antibody titres <8 during the first 4 weeks of infection, after which one case showed an elevation in antibody titre for the first time, 13 weeks after the onset of disease. In contrast, all non-proven cases had antibody titres of < or = 64, and only one case developed a four-fold or greater rise in titre. These results indicate that MPAT is a useful method for the laboratory diagnosis of suspected legionella pneumonia, although several false-negative cases were observed. This suggests that the previously established MPAT criteria may require modification, possibly to slightly lower values. These data also indicate that serial examination over the first month of infection may be necessary for serodiagnosis of legionella pneumonia, especially in patients treated with corticosteroids.

Agglutination Tests↗

PubMed1998

Is a hypertensinogenic factor present in the kidney of hypertensive dahl rats?

1. Early studies suggest that hypertension in Dahl salt-sensitive (S) rats is related to an uncommon humoral factor that may be released from the kidney. 2. To investigate whether the kidney releases a hypertensinogenic factor for developing salt-induced hypertension in S rats, we examined a pressor effect, or vascular contractive activity of a kidney extract from S rats using a conscious recipient rat or an isolated aortic ring. 3. Donor S and Dahl salt-resistant (R) rats were fed a 0.4 or 8% NaCl diet for 4 weeks and were then used to provide four kinds of kidney extracts (S-0.4%, S-8%, R-0.4%, R-8%). The systolic arterial pressure (SAP) was significantly increased in donor S rats fed an 8% NaCl diet compared with other donor rat groups. 4. All four types of kidney extract increased mean arterial pressure (MAP) in a recipient rat fed a 0.4% NaCl diet. However, the increase in MAP observed following infusion of the S-8% extract was the least of all groups. An angiotensin AT1 receptor antagonist, CV-11974, abolished any pressor effect of all kidney extracts. In an in vitro experiment, all four types of kidney extract evoked contractile responses in aortic rings, but elicited no significant difference in aortic ring contractile force. 5. These results suggest that the kidney of S rats may not release an active hypertensinogenic factor that would cause salt-induced hypertension.

Angiotensin Receptor Antagonists↗

PubMed1998

Efflux transport of tolbutamide across the blood-brain barrier.

In an attempt to determine the reason for the low brain distribution of tolbutamide, we have demonstrated the transport of tolbutamide from the brain to the blood via a non-P-glycoprotein efflux transport system which is inhibited by sulphonamides. We evaluated the directional transport of tolbutamide across the blood-brain barrier by means of an in-vivo brain-tissue distribution study and experiments on in-vitro transcellular transport and uptake in cultured mouse-brain capillary endothelial cells (MBEC4). The brain-to-unbound-plasma concentration ratio of [14C]tolbutamide increased in the presence of high concentrations of unlabelled tolbutamide or sulphonamide at steady-state in-vivo. The brain-to-blood concentration ratios of [14C]tolbutamide were very low compared with that of [3H]propranolol obtained by in-vivo integration plot analysis. From the in-vitro transcellular transport study using a monolayer of MBEC4 cells, we found that the abluminal-to-luminal flux of [14C]tolbutamide was higher than the reverse flux. Both luminal-to-abluminal and abluminal-to-luminal transport of tolbutamide were saturable. The maximum transport rate (Jmax), the half-saturation concentration (Kt), and the first-order rate constant (kd) were 65.9 +/- 29 pmol min(-1) (mg protein)(-1), 7.54 +/- 4.4 microM, and 4.89 +/- 0.34 microL min(-1) (mg protein)(-1), respectively, for luminal-to-abluminal transport, and 128 +/- 66 pmol min(-1) (mg protein)(-1), 5.59 +/- 4.2 microM, and 4.43 +/- 0.86 microL min(-1) (mg protein)(-1) , respectively, for abluminal-to-luminal transport. At therapeutic plasma concentrations of tolbutamide (1-16.9 microM), the efflux rate would be faster than the influx rate. The estimated net efflux was consistent with the very low in-vivo brain distribution of tolbutamide. The efflux process observed in MBEC4 cells was inhibited by sulphonamides such as sulphaphenazole, sulphamethoxazole and sulpha-dimethoxine whereas the steady-state uptake of [14C]tolbutamide was not affected by either cyclosporin or verapamil, specific inhibitors of P-glycoprotein. These findings suggest that tolbutamide is partly transported from the brain via the non-P-glycoprotein-efflux transport system, which is inhibited by sulphonamides.

Animals↗

PubMed1998

Blockade of neuronal nitric oxide synthase alters the baroreflex control of heart rate in the rabbit.

In previous studies we used NG-nitro-L-arginine (L-NNA) to investigate the role of nitric oxide (NO) in baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA). L-NNA increased resting mean arterial pressure (MAP), decreased HR, and did not change or slightly decreased RSNA. These changes complicated the assessment of the central effects of NO on the baroreflex control of HR and RSNA. Therefore, in the present study the effects of the relatively selective neuronal NO synthase inhibitor 7-nitroindazole (7-NI) on the baroreflex control of HR and RSNA were investigated in rabbits. Intraperitoneal injection of 7-NI (50 mg/kg) had no effect on resting HR, MAP, or RSNA. 7-NI significantly reduced the lower plateau of the HR-MAP baroreflex curve from 140 +/- 4 to 125 +/- 4 and from 177 +/- 10 to 120 +/- 9 beats/min in conscious and anesthetized preparations, respectively (P < 0.05). In contrast, there was no significant difference in the RSNA-MAP curves before and after 7-NI administration in conscious or anesthetized preparations. These data suggest that blockade of neuronal NO synthase influences baroreflex control of HR but not of RSNA in rabbits.

Animals↗

PubMed1998

Suppression of renal sympathetic nerve activity during portal vein infusion of hypertonic saline.

Sodium ions absorbed from the intestine are postulated to act on the liver to reflexly suppress renal sympathetic nerve activity (RSNA), resulting in inhibition of sodium reabsorption in the kidney. To test the hypothesis that the renal sympathoinhibitory response to portal venous NaCl infusion involves an action of arginine vasopressin (AVP) at the area postrema, we examined the effects of portal venous infusion of hypertonic NaCl on RSNA before and after lesioning of the area postrema (APL) or after pretreatment with an AVP V1 receptor antagonist (AVPX). Rabbits were chronically instrumented with portal and femoral venous catheters, femoral arterial catheters, and renal nerve electrodes. Portal venous infusion of 9.0% NaCl (0.02, 0.05, 0.10, and 0.15 ml.kg-1.min-1 of 9.0% NaCl for 10 min) produced a dose-dependent suppression of RSNA (-12 +/- 3, -34 +/- 3, -62 +/- 5, and 80 +/- 2%, respectively) that was greater than that produced by femoral vein infusion of 9.0% NaCl (2 +/- 3, -3 +/- 2, -12 +/- 4, and -33 +/- 3%, respectively). The suppression of RSNA produced by portal vein infusion of 9.0% NaCl was partially reversed by pretreatment with AVPX (-9 +/- 3, -20 +/- 3, -41 +/- 4, and -55 +/- 4%, respectively) and by APL (-11 +/- 2, -25 +/- 2, -49 +/- 3, and -59 +/- 6%, respectively). There were no significant differences between the effects of AVPX and APL, and the effect of APL was not augmented by AVPX. These results indicate that the suppression of RSNA due to portal venous infusion of 9.0% NaCl involves an action of AVP via the area postrema.

Animals↗