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H Matsuo

Publications and source records attributed to H Matsuo.

At least 55 records · Page 3Linked to original sources
PubMed2001

Human cystinuria-related transporter: localization and functional characterization.

BACKGROUND: Cystinuria has been proposed to be an inherited defect of apical membrane transport systems for cystine and basic amino acids in renal proximal tubules. Although the mutations of the recently identified transporter BAT1/b(0,+)AT have been related to nontype I cystinuria, the function and localization of human BAT1 (hBAT1)/b(0,+)AT have not been well characterized. METHODS: The cDNA encoding hBAT1 was isolated from human kidney. Fluorescence in situ hybridization was performed to map the hBAT1 gene on human chromosomes. Tissue distribution and localization of expression were examined by Northern blot and immunohistochemical analyses. hBAT1 cDNA was transfected to COS-7 cells with rBAT cDNA, and the uptake and efflux of 14C-labeled amino acids were measured to determine the functional properties. The roles of protein kinase-dependent phosphorylation were investigated using inhibitors or activators of protein kinases. RESULTS: The hBAT1 gene was mapped to 19q12-13.1 on the human chromosome, which is the locus of nontype I cystinuria. hBAT1 message was expressed predominantly in kidney. hBAT1 protein was localized in the apical membrane of proximal tubules in human kidney. When expressed in COS-7 cells with a type II membrane glycoprotein rBAT (related to b(0,+)-amino acid transporter), hBAT1 exhibited the transport activity with the properties of amino acid transport system b(0,+), which transported cystine as well as basic and neutral amino acids presumably via a substrate exchange mechanism. BAT1-mediated transport was reduced by the protein kinase A activator and enhanced by the tyrosine kinase inhibitor. CONCLUSIONS: hBAT1 exhibited the properties expected for a transporter subserving the high-affinity cystine transport system in renal proximal tubules. The hBAT1 gene was mapped to the locus of nontype I cystinuria, confirming the involvement of hBAT1 in cystinuria.

ATP-Binding Cassette Transporters↗
PubMed2001

Plasmapheresis affects T helper type-1/T helper type-2 balance of circulating peripheral lymphocytes.

Plasmapheresis not only removes humoral factors, but may also modulate cellular immunity. We investigated whether plasmapheresis influenced T helper type-1/T helper type-2 (Th1/Th2) cytokine-producing-cell balance in 3 patients with neuroimmunological disease. The production of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and IL-4 in the culture supernatant of peripheral blood mononuclear cells stimulated by anti-CD3 and anti-CD28 was assayed. In 2 of 3 patients, plasmapheresis (immunoadsorption or plasma exchange) reduced Th1/Th2 cytokine ratio. The results may suggest that plasmapheresis induces a shift of Th1/Th2 balance in peripheral blood.

Humans↗
PubMed2001

Isolation and characterization of the genes up-regulated in isolated neurons by aged garlic extract (AGE).

Aged garlic extract (AGE) produces neurotrophic effects on cultured fetal rat hippocampal neurons. These studies examined the molecular events triggered by AGE that might account for a suppression of neuronal cell death. Genes differentially expressed by the addition of AGE in primary cultured hippocampal neurons isolated from fetal rat brain were screened using mRNA differential display. Four cDNA clones were significantly enhanced at their transcriptional level; they were designated as #24, #110, #153 and #155. Quantitative reverse transcription-polymerase chain reaction (RT-PCR), as well as dot-blot hybridization combined with RT-PCR, confirmed that the transcription from these four genes was elevated at least twofold, particularly the mRNA of #153, which was increased >20 times 72 h after the addition of AGE. A homology search of the respective cDNA sequences in the DNA database revealed that #153 is an alpha 2-microglobulin-related protein (alpha 2MRP) gene. The others genes were not identified. Induction of the alpha 2MRP gene expression occurred within 24 h after addition of AGE. These findings suggest a possible mechanism by which AGE may regulate gene expression and bring about a neurotrophic effect. Further, our results suggest that alpha 2MRP may function at the initial step of the molecular events triggered by AGE and play an important role in the survival of hippocampal neurons.

Animals↗
PubMed2001

Gramine increase associated with rapid and transient systemic resistance in barley seedlings induced by mechanical and biological stresses.

Systemic acquired resistance (SAR) is one of the intriguing issues for studying the mechanism in signal transduction system in a whole plant. We found that SAR and increase of an antifungal compound were induced rapidly and transiently in barley (Hordeum vulgare L. cv. Goseshikoku) by mechanical and biological stresses. One of the major antifungal compounds was identified as an indole alkaloid, gramine (N,N-dimethyl-3-aminomethylindole), by mass spectrum and NMR analyses. Gramine is well known as a constitutive compound of barley, but it increased significantly in the primary and secondary leaves of barley seedlings within 12 h after pruning or inoculating with the powdery mildew fungi of barley (Blumeria graminis f.sp. hordei) and wheat (B. graminis f.sp. tritici). However, in the leaf detached from unwounded seedlings or in the leaf inoculated with the barley powdery mildew fungus, gramine did not increase at all. In the water droplets contacted with barley leaves, the amount of leaked gramine increased dependently upon the time after the seedling was injured mechanically. We also found a tight correlation between gramine increase and enhancement of resistance to the barley powdery mildew fungus in barley leaves treated with an endogenous elicitor. Furthermore, such a systemic resistance was not observed in a barley cultivar Morex that lacks the biosynthetic pathway of gramine. From these results, we conclude that gramine is the excellent marker in rapid and transient systemic acquired resistance in barley.

Alkaloids↗
PubMed2001

Molecular forms of plasma and urinary adrenomedullin in normal, essential hypertension and chronic renal failure.

OBJECTIVES: Human adrenomedullin precursor is converted to glycine-extended adrenomedullin (AM-Gly), an intermediate inactive form of adrenomedullin. Subsequently, AM-Gly is converted to active form of mature adrenomedullin (AM-m). The aim of the present study was to investigate (i) whether sex or age influences plasma and urinary AM-m and AM-Gly levels in normal subjects; (ii) the daytime variability of plasma AM-m and AM-Gly levels in normal subjects; (iii) AM-m and AM-Gly levels and its ratio in plasma and urine in normal subjects, individuals with essential hypertension (HT), and chronic renal failure (CRF); and (iv) the ratio of AM-m and AM-total (T) in plasma of various veins and aorta. METHODS: We measured plasma levels and urinary excretions of AM-m, AM-Gly and AM-T (AM-m + AM-Gly) by recently developed immunoradiometric assay in normal subjects (n = 81), HT (n = 28) and CRF (n = 30). We also determined the molecular forms of plasma adrenomedullin taken from various sites during angiography in patients with suspected renovascular hypertension (n = 9). RESULTS: There were no differences in plasma and urinary excretions of two molecular forms of adrenomedullin among sexes or ages in normal subjects. There was no daytime variation of plasma two molecular forms of adrenomedullin in normal subjects. Plasma AM-m, AM-Gly and AM-T levels were increased in patients with HT and CRF compared with normal subjects, whereas urinary AM-m, AM-Gly and AM-T excretions were decreased in patients with HT and CRF compared with normal subjects. Urinary AM-m: AM-T ratios were significantly higher than plasma AM-m: AM-T ratios. Plasma AM-m and AM-T levels taken from various veins were similar, and they were significantly higher than those of aorta, although there were no differences in plasma AM-Gly levels between aorta and veins. CONCLUSIONS: These results suggest that in normal subjects, and individuals with HT and CRF: (i) plasma and urinary excretions of AM-m and AM-Gly are not affected by age or sex; (ii) AM-m in parallel with AM-Gly is increased; (iii) urine contains a higher percentage of active adrenomedullin than plasma; and (iv) plasma AM-m may be partly metabolized in the lung.

Adrenomedullin↗
PubMed2001

Regulation of endothelin-1 production in cultured rat vascular smooth muscle cells.

Endothelin-1 (ET-1) is secreted from all rat vascular smooth muscle cells (VSMCs) examined, in addition to endothelial cells (ECs). An average secretion rate of ET-1 from rat VSMCs was determined to be 10% that excreted from ECs. We examined the effects of 22 substances on ET-1 secretion from VSMCs and compared them with those from ECs. Transforming growth factor-beta1 (TGF-beta), acidic and basic fibroblast growth factors, epidermal growth factor, angiotensin II, and adrenaline stimulated ET-1 secretion from VSMCs, whereas forskolin, thrombin, and platelet-derived growth factor-BB reduced it. Only TGF-beta and phorbol ester elicited consistent effects on ET-1 secretion from VSMCs and ECs. Regulation of ET-1 and adrenomedullin secretion from VSMCs was distinctly different. These data suggest that ET- 1 production in VSMCs is regulated by a mechanism separate from that in ECs and from adrenomedullin production in VSMCs. Chromatographic analysis showed immunoreactive ET-1 secreted from VSMCs was mainly composed of big ET- 1, whereas approximately 90% of that from ECs was ET-1. By TGF-beta stimulation of VSMCs, the ratio of big ET-1 to ET-1 was further increased. Because big ET-1 is converted into ET-1 only on the surface of the ECs in the culture system, big ET-1 secreted from the VSMCs may function as a mediator transmitting a signal from VSMCs to ECs in vivo.

Adrenomedullin↗
PubMed2001

Prevention of cerebral thromboembolism by low-dose anticoagulant therapy in atrial fibrillation with mitral regurgitation.

Controversy exists regarding the influence of mitral regurgitation (MR) on thromboembolic risk in patients with atrial fibrillation. We aimed to investigate retrospectively a reduction of risk for stroke due to MR in atrial fibrillation and to evaluate the effectiveness of low-intensity anticoagulation therapy. In 313 patients with atrial fibrillation, transthoracic echocardiography was performed and MR was graded. Between the groups with no or mild MR (n = 209) and with moderate or severe MR (n = 104), age, sex, treatment, history of diabetes, hypertension, hyperlipemia and mitral stenosis, and previous stroke were compared. No significant differences in clinical characteristics, treatment, or history were observed between the two groups. The incidence of thromboembolism was significantly higher in the group with no MR (48 patients [23%]) than in the group with MR (14 patients [13%], p < 0.05). In the MR group, previous stroke was frequently observed in patients without warfarin treatment (11 of 51 patients) compared with patients with low-dose warfarin treatment (international normalized ratio of 1.6-1.8) (3 of 53 patients, p < 0.05). Consequently, the thromboembolic event was markedly prevented by low-dose warfarin treatment.

Aged↗
PubMed2001

Role of increased circulating and renal adrenomedullin in rats with malignant hypertension.

Although it has been reported that the circulating adrenomedullin (AM) level is elevated in hypertension and renal failure, the pathophysiological significance of circulating and intrarenal AM in malignant hypertension remains unknown. We investigated the circulating and intrarenal AM system in rats with malignant hypertension by measuring the plasma level, renal tissue level, and mRNA abundance of AM and the mRNA abundance of AM receptor. We also investigated the effects of intravenously infused calcitonin gene-related peptide (CGRP)-(8-37), an antagonist of AM, on the hemodynamics and renal tubular function. We studied the following four groups: control Wistar-Kyoto rats (WKY), control spontaneously hypertensive rats (C-SHR), salt-loaded SHR (S-SHR), and DOCA-salt SHR (D-SHR). After 3 wk of DOCA treatment, D-SHR developed malignant hypertension. D-SHR were characterized by higher blood pressure, kidney weight, urinary protein excretion and blood urea nitrogen, and lower creatinine clearance compared with the other three groups. The plasma AM level and urinary excretion of AM were markedly higher in D-SHR than in the other three groups. In the kidney, the tissue AM level and the expression of AM mRNA in the renal medulla were significantly increased in D-SHR compared with the other three groups, whereas there were no significant differences in these levels in the renal cortex among the four groups. In the renal AM receptor system, the expression of the gene for receptor activity modifying protein 3 was significantly increased in the renal medulla in D-SHR compared with the other three groups. An immunohistochemical study revealed that AM immunostaining in renal collecting duct cells and distal tubules was more intense in D-SHR than in the other three groups. After CGRP-(8-37) infusion, blood pressure increased significantly and urinary sodium excretion and urine flow decreased significantly only in D-SHR. These results suggest that the increased circulating AM and renal AM and the increased expression of the mRNA for AM and its receptor may at least partly compensate for the malignant hypertensive state in certain forms of malignant hypertension via the hypotensive, natriuretic, and diuretic actions of AM.

Adrenomedullin↗
PubMed2001

Alterations of intrarenal adrenomedullin and its receptor system in heart failure rats.

Calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion.

Adrenomedullin↗
PubMed2001

Angiotensin-converting enzyme inhibition with enalapril slows progressive intima-media thickening of the common carotid artery in patients with non-insulin-dependent diabetes mellitus.

BACKGROUND AND PURPOSE: Whether angiotensin-converting enzyme (ACE) inhibitors have any clinically significant antiatherogenic effects in humans remains unproven. We undertook a prospective randomized clinical trial of 98 patients with non-insulin-dependent diabetes mellitus (NIDDM) to examine the efficacy of ACE inhibition with enalapril for preventing intima-media (IM) thickening of the carotid wall as measured ultrasonographically. METHODS: Ninety-eight NIDDM patients were randomly assigned either to enalapril at 10 mg/d (n=48) or to a control group (n=50); the planned duration of the trial was 2 years. All patients were seen at baseline (study entry) and 2 subsequent formal annual evaluations, in addition to standard clinical management for NIDDM. IM thickening and vascular lumen diameters were determined for all patients on the basis of baseline and 2 subsequent annual evaluations with carotid ultrasonography. We performed an intent-to-treat analysis to assess changes in IM thickening over the course of the study. RESULTS: Annual IM thickening measurements of the right and left common carotid arteries were 0.01+/-0.02 and 0.01+/-0.02 mm/y in the enalapril-treated group and 0.02+/-0.03 and 0.02+/-0.02 mm/y in the control group, respectively (P<0.05). From regression analysis, annual IM thickening was found to be predicted by enalapril use, sex, and insulin use (F(3,94)=3.86, P=0.012). When we controlled for these other variables, enalapril use reduced annual IM thickening of right and left common carotid arteries by 0.01+/-0.004 mm/y relative to the control group over the course of this study. CONCLUSIONS: Long-term treatment with an ACE inhibitor (enalapril) slows progressive IM thickening of the common carotid artery in NIDDM patients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Improvement of left ventricular diastolic dynamics in prediabetic stage of a type II diabetic rat model after troglitazone treatment.

Troglitazone, an oral antidiabetic agent, has hypoglycemic effects in insulin-resistant animal models and humans. This study was conducted to evaluate its effect on left ventricular diastolic dynamics of a spontaneous diabetic (DM) rat model. Twenty DM rats and 20 age-matched nonDM rats were used, and 10 of each group were treated with troglitazone as a 0.2% food admixture for 10 weeks. At 5 and 15 weeks of age, Doppler echocardiography and M-mode echocardiography were performed. Troglitazone treatment significantly improved the left ventricular diastolic dynamics of DM rats: deceleration time (msec) of early diastolic inflow decreased significantly (treated 52 +/- 3 vs untreated 64 +/- 5, p = 0.0002), and peak velocity of early transmitral inflow (cm/sec) increased significantly (treated 96 +/- 7 vs untreated 86 +/- 8, p = 0.0216). The data suggest that troglitazone improves left ventricular diastolic dynamics of a DM rat model at prediabetic stage.

Animals↗
PubMed2001

Contrast harmonic power Doppler imaging of congenital ventricular diverticulum--a case report.

A case of an 81-year-old woman with a left ventricular diverticulum who underwent myocardial contrast echocardiography is reported. After administration of the contrast agent, a pulsed Doppler flow measurement clearly revealed the biphasic waveform of the ejection flow in the pre-systolic and systolic phase at the ostium of the diverticular cavity. A harmonic power Doppler image showed that part of the diverticulum wall had similar acoustic properties to the ventricular septal wall. Intracardiac blood flow and myocardial perfusion could be clearly evaluated and a ventricular diverticulum was correctly diagnosed using contrast echocardiography.

Aged↗
PubMed2001

Up-regulation by IGF-I of proliferating cell nuclear antigen and Bcl-2 protein expression in human uterine leiomyoma cells.

IGF-I has been reported to play a role in regulating proliferation of human leiomyoma cells. There is, however, little evidence to suggest that IGF-I inhibits apoptosis in the leiomyoma cells. The present study was conducted to elucidate whether IGF-I affects apoptosis and Bcl-2 protein expression, an apoptosis-inhibiting gene product, in cultured leiomyoma cells. In addition, we examined the effect of IGF-I on proliferating cell nuclear antigen (PCNA) expression in cultured leiomyoma cells. Isolated human leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% FBS for 120 h and then stepped down to serum-free conditions for an additional 72 h in the absence or presence of graded concentrations of IGF-I (1.0, 10, and 100 ng/ml). The effects of IGF-I on Bcl-2 protein and PCNA expression in cultured leiomyoma cells were assessed by Western immunoblot analysis and immunocytochemical staining, whereas the effects of IGF-I on the cell viability and apoptosis of the cultured cells were determined by 3-(4,5-dimethylatriazol-2-yl)-2,5diphenyltetrasodium bromide (MTT) assay and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling assay, respectively. Immunocytochemical staining demonstrated that IGF-I treatment resulted in the increase in PCNA labeling index in cultured leiomyoma cells in a dose-dependent manner. Immunoblot analysis of proteins extracted from the cultured leiomyoma cells revealed that the addition of IGF-I (10 and 100 ng/ml) significantly increased the expression of 35-kDa immunoreactive PCNA and 26-kDa Bcl-2 protein, compared with those in control cultures. Cell survival and proliferation of cultured leiomyoma cells, assessed by MTT assay, was significantly augmented by IGF-I treatment, compared with those of control cultures. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling assay showed that the apoptosis-positive rate of leiomyoma cells treated with IGF-I was significantly decreased, compared with that in control cultures. The present results suggest that IGF-I plays crucial roles in leiomyoma cell growth, not only in promoting the proliferative potential by up-regulation of PCNA expression but also in down-regulating apoptosis by up-regulation of Bcl-2 protein expression in leiomyoma cells.

Adult↗
PubMed2001

Tumor necrosis factor-alpha expression in human uterine leiomyoma and its down-regulation by progesterone.

Although tumor necrosis factor-alpha (TNFalpha) has been shown mainly to inhibit proliferation and induce apoptosis in a variety of cells, no information is available regarding whether human leiomyoma cells express TNFalpha. In the present study, we examined the expression of TNFalpha in leiomyomas, in comparison with that in the adjacent normal myometrium, using immunohistochemical staining and Western immunoblot analysis with a polyclonal antibody to human TNFalpha. Furthermore, we investigated the effect of sex steroid hormones on TNFalpha expression in leiomyoma cells cultured under serum-free, phenol red-free conditions. Immunohistochemical staining showed that TNFalpha expression in leiomyoma cells was higher than that in the adjacent normal myometrial cells, being more abundant in the proliferative phase than in the secretory, progesterone (P4)-dominated, phase of the menstrual cycle. TNFalpha expression in leiomyoma cells in pregnant uterus was scarce. Western immunoblot analyses of leiomyoma and normal myometrial tissue extracts revealed that TNFalpha, with a molecular mass of 17.3 kDa, was abundantly present in leiomyoma tissue extracts, relative to normal myometrial tissue extracts, and that TNFalpha expression in leiomyoma cells was most abundant in the proliferative phase of the menstrual cycle, less abundant in the secretory phase, and least abundant in pregnant uterus; whereas no such changes in TNFalpha expression were noted in the normal myometrium. In monolayer cultures of uterine leiomyoma cells under serum-free conditions, addition of P4 (3.18 x 10(-7) mol/L) resulted in a decrease in TNFalpha expression in the cells, relative to that in control cultures, whereas treatment with 17beta-estradiol (3.67 x 10(-8) mol/L) did not affect the TNFalpha expression in the cells. The concentrations of sex steroids used were within the physiological tissue concentrations noted in leiomyoma and myometrium. The present results suggest that the abundant expression of TNFalpha may be a molecular basis characteristic of leiomyomas in the human uterus and that P4 may play a vital role in down-regulating the expression of TNFalpha in human uterine leiomyoma.

Adult↗
PubMed2001

In-vivo kinetics of the interaction between midazolam and erythromycin in rats, taking account of metabolic intermediate complex formation.

To predict, quantitatively, the extent of drug interaction during repeated administration of a metabolic inhibitor, we analysed the effects of erythromycin treatment under several regimens on the area under the concentration curve (AUC) of midazolam in rats. Midazolam was administered into the portal vein 12 h after erythromycin treatment for 1, 2 or 3 days, or 12, 24, 36, 48, 72 and 96 h after erythromycin treatment for 4 days, and the plasma-concentration profiles of midazolam were analysed to assess the AUC. Moreover, the contents of total cytochrome P450 and inactive metabolic intermediate (MI) complex were simultaneously quantitated. While the AUC value of midazolam was not affected by the administration of erythromycin for 1 day, repeated administration of erythromycin evoked an increase in AUC ratio (AUC in erythromycin-treated rats/AUC in vehicle-treated rats), which reached a maximum value of 1.99 at 12 h after 4 days' treatment with erythromycin. The total content of cytochrome P450 in liver microsomes was unaffected by erythromycin treatment. Although the MI complex was undetectable after 1 day's treatment with erythromycin, its content increased with duration of erythromycin treatment, and the complex disappeared after the end of erythromycin treatment with a half-life of 12.3 h. In conclusion, the interaction between erythromycin and midazolam could be well predicted when the formation of MI complex in the liver was taken into account.

Animals↗
PubMed2001

The active molecular form of plasma adrenomedullin is extracted in the pulmonary circulation in patients with mitral stenosis: possible role of adrenomedullin in pulmonary hypertension.

Adrenomedullin (AM), a novel hypotensive peptide, preferentially dilates pulmonary vessels rather than systemic vessels. This suggests the possibility that AM is a circulating hormone which participates in regulation of the pulmonary circulation. A recent study revealed that two molecular forms of AM, i.e. a mature, active form of AM (AM-m) and an intermediate, inactive, glycine-extended form of AM (AM-Gly), circulate in human plasma. In the present study we investigated the production and clearance sites and pathophysiological significance of the two molecular forms of AM in the pulmonary circulation in patients with mitral stenosis. We measured the plasma levels of AM-m and total AM (AM-T; AM-m+AM-Gly) using a recently developed specific immunoradiometric assay, and thus calculated plasma AM-Gly levels, in blood samples obtained from the femoral vein, pulmonary artery, left atrium and aorta of 28 consecutive patients with mitral stenosis (20 females and eight males; age 53+/-10 years). Patients with mitral stenosis had significantly higher venous concentrations of AM-T, AM-Gly and AM-m than age-matched normal controls (AM-T, 15.9+/-2.5 and 10.6+/-2.1 pmol/l respectively; AM-Gly, 14.0+/-2.1 and 9.8+/-1.9 pmol/l respectively; AM-m, 1.9+/-0.6 and 1.1+/-0.3 pmol/l respectively; each P<0.001). There was a significant decrease in the concentrations of AM-m and AM-T between the pulmonary artery and the left atrium (AM-T, 16.1+/-2.7 and 14.0+/-2.4 pmol/l respectively; AM-m, 2.0+/-0.6 and 0.7+/-0.2 pmol/l respectively; each P<0.001); however, there were no differences in plasma AM-Gly levels between the pulmonary artery and the left atrium (14.1+/-2.3 and 13.5+/-2.3 pmol/l respectively). The venous concentrations of AM-m, AM-Gly and AM-T showed similar correlations with mean pulmonary artery pressure (AM-T, r=0.67; AM-Gly, r=0.63; AM-m, r=0.59; each P<0.001) and total pulmonary vascular resistance (AM-T, r=0.77; AM-Gly, r=0.70; AM-m, r=0.75; each P<0.001). These results suggest that the plasma concentration of AM-m is increased in parallel with those of AM-Gly and AM-T, and that the main site for clearance of AM-m from the plasma is the lung; the extracted AM-m in the lungs may help to attenuate the increased pulmonary arterial resistance in secondary pulmonary hypertension due to mitral stenosis.

Adrenomedullin↗
PubMed2001

Prediction of midazolam-CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data.

The extent of decreases in apparent hepatic clearance and intrinsic hepatic clearance of midazolam (MDZ) after intravenous administration of MDZ with concomitant oral administration of cimetidine (CIM), itraconazole (ITZ), or erythromycin (EM) was predicted using plasma unbound concentrations and liver unbound concentrations of inhibitors. When MDZ was concomitantly administered with CIM, the observed increase in MDZ concentration was successfully predicted using inhibition constants assessed by human liver microsome and liver-to-plasma unbound concentration ratios in rats. However, the extent of interaction with ITZ or EM was still underestimated even taking into account the concentrative uptake of inhibitors into liver. We could predict the degree of "mechanism-based" inhibition by EM on the hepatic metabolism of MDZ, after repeated administration of EM, by a physiological model incorporating the amount of active enzyme as well as the concentration of inhibitor. The maximum inactivation rate constant and the apparent inactivation constant of EM on MDZ metabolism were 0.0665 min(-1) and 81.8 microM, respectively. These kinetic parameters for the inactivation of the enzyme were applied to the physiological model with pharmacokinetic parameters of EM and MDZ obtained from published results. Consequently, we estimated that cytochrome P450 3A4 in the liver after repeated oral administration of EM was inactivated, resulting in 2.6-fold increase in the plasma concentration of MDZ. The estimated extent of increase in MDZ concentration in our study correlated well with the observed value based on metabolic inhibition by EM from published results.

Anesthetics, Intravenous↗