Search PubMed⌕ Search

Biomedical subjects

Hiroshi Inoue

Publications and source records attributed to Hiroshi Inoue.

At least 91 records · Page 5Linked to original sources
PubMed2005

Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol.

In patients routinely treated with metoprolol, influences of CYP2D6 genotype on the response of heart rate to isoproterenol (IP) were studied at its peak and trough concentrations and were compared with those of bisoprolol. In 72 patients treated with metoprolol or bisoprolol, CYP2D6 genotype (ie, CYP2D6*1, *2, *4, *5, *10, and *14) was determined. No patients except one who was heterozygous for CYP2D6*5 carried the null alleles of CYP2D6. The homozygote frequency for CYP2D6*10 was relatively high (19.4%) and these patients had greater peak and trough plasma concentrations of metoprolol than the other patients. Isoproterenol-induced percentage increases in heart rate were 58% and 38% less at the low and high rate of isoproterenol infusion (0.02 and 0.04 microg/kg/min), respectively, in patients homozygous for CYP2D6*10 than in the other patients at the trough, but not at the peak concentrations. In contrast, CYP2D6 genotype did not affect plasma concentrations of bisoprolol and the extent of its beta-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant beta-adrenergic inhibition independent of CYP2D6 genotype.

Adrenergic beta-Antagonists↗
PubMed2005

Intraductal tubular adenoma of the pancreas, pyloric gland type: a clinicopathologic and immunohistochemical study of 6 cases.

The intraductal tubular adenoma (ITA), pyloric gland type, of the pancreas is an uncommon benign tumor, akin to the pyloric gland type adenoma of the gallbladder. We report 6 cases of ITA of the pancreas: 3 male and 3 female aged 50 to 79 years (mean, 63.5 years; median, 65 years); all were examined clinicopathologically. Four patients showed no symptoms, but appetite loss and/or general fatigue presented in two. Grossly, all tumors formed a localized polypoid mass protruding into the lumen of the dilated pancreatic duct. Five of the six tumors were found within the main duct, and the other arose within the branch duct of the pancreas. Microscopically, the tumors were composed of closely packed tubular glands resembling pyloric type glands. They were lined by columnar or cuboidal epithelial cells with foci of mild to moderate dysplastic change. In 2 cases, the adjacent pancreas showed foci of intraductal papillary-mucinous adenoma. Histochemically, the tumors largely showed neutral mucin with a lesser amount of acidic mucin made up mainly of sialomucin. Endocrine cells were found in five tumors. Immunohistochemically, all tumors were labeled with M-GGMC-1 and MUC6, whereas MUC1 and MUC2 stains were negative. Pepsinogen II was positive in 5 tumors; thus, the results displayed a pattern of differentiation similar to those of ordinary gastric pyloric or metaplastic pyloric glands. DPC4 expression was maintained in all tumors and p53-positive nuclei were hardly encountered. All patients are alive with no evidence of disease 3 to 10.5 years after surgical resection.

Adenoma↗
PubMed2005

Effects of uninephrectomy on renal structural properties in spontaneously hypertensive rats.

1. To investigate effects of a reduction in nephron numbers on renal structural properties in hypertension, either unilateral nephrectomy (UNX) or sham operation (SO) was performed at 5 weeks of age in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (n = 9 for each operation for each strain). 2. At 10-12 weeks of age, flow-pressure (F-P) and pressure-glomerular filtration rate (P-GFR) relationships were determined for maximally vasodilated, perfused kidneys. Kidneys were then perfusion fixed for histological analysis. 3. In the SO groups, the slope of F-P (minimal renal vascular resistance, reflecting overall luminal dimensions of pre- and post-glomerular vasculature) was greater in SHR than in WKY rats. The threshold pressure for beginning filtration at P-GFR (preglomerular to post-glomerular vascular resistance ratio) was higher in SHR than in WKY rats, but the slope of P-GFR (glomerular filtration capacity) did not differ between the two strains. These results suggest that vascular narrowing occurred, especially in the preglomerular resistance vessels in the kidneys of SHR, although glomerular filtration capacity was normal. 4. In UNX animals, the following results were obtained: (i) the slope of F-P was not affected in either strain; (ii) the pressure for beginning filtration at P-GFR was unchanged in WKY rats, but was decreased in SHR; (iii) the slope of P-GFR increased in WKY rats, but a compensatory adaptive increase was missing in SHR; and (iv) histologically, small increases in the luminal cross-sectional area of interlobular arteries and glomerular tuft area were observed in both strains. However, the increase in vascular lumen was more pronounced in SHR, whereas glomerular enlargement was greater in WKY rats. 5. These results suggested that UNX attenuates vascular narrowing of the preglomerular resistance vessels and glomerular structural adaptations to UNX (i.e. increased filtering capacity and glomerular enlargement) are impaired in SHR.

Animals↗
PubMed2005

Efficacy and safety of intravenous theophylline administration for treatment of mild acute exacerbation of bronchial asthma.

OBJECTIVE: The present study was designed to evaluate the efficacy and safety of intravenously administered theophylline (IAT) for the treatment of an acute exacerbation of bronchial asthma. The theophylline was solubilized and not combined with ethylenediamine. METHODOLOGY: The subjects were 22 asthmatic patients with mild acute exacerbation of bronchial asthma. All patients had been taking oral sustained-release theophylline and their serum concentrations of theophylline were measured. The 16 patients whose serum theophylline concentrations were <13 microg/mL were randomly selected and treated with IAT (200 mg theophylline in 200 mL saline) for 2 h. Six patients were randomly selected as controls and received 200 mL of saline. Pulmonary function and asthma severity (Borg scale) before and after treatment were measured. RESULTS: After IAT, both PEF (before IAT, 313+/-79 L/min; after IAT, 335+/-107; P<0.05) and FEV(1) (before IAT, 1.66+/-0.47 L; after IAT, 1.83+/-0.44; P<0.05) increased significantly. Furthermore, their severity of asthma as assessed by the Borg scale (before IAT, 2.5+/-1.2; after IAT, 1.3+/-1.0; P<0.05) improved significantly. In contrast, neither FEV(1), PEF, severity of asthma or Borg scale changed significantly in the group who only received saline. None of the patients treated in this study had any adverse effects. CONCLUSION: These results suggest that IAT is useful for patients with mild acute exacerbation of bronchial asthma and is safe if serum theophylline concentrations are measured.

Acute Disease↗
PubMed2005

Enalapril preserves sinus node function in a canine atrial fibrillation model induced by rapid atrial pacing.

METHODS AND RESULTS: Seventeen beagles were pretreated with either placebo (group I, n = 9) or enalapril 1 mg/kg/day (group II, n = 8) and paced at 500/min from the right atrial appendage for 4 weeks. Every week, corrected sinus node recovery time (CSNRT) and sinus cycle length (SCL) were measured. Quantitative analysis of interstitial fibrosis (IF) and adipose tissue (AT) in the SN was performed with Masson's trichrome stain, and apoptosis of the sinus nodal cells were detected with terminal deoxynucleotidyl transferase nick end-labeling. In group I, rapid atrial pacing prolonged both CSNRT and SCL. After 4 weeks of pacing, CSNRT and SCL were significantly shorter in group II (CSNRT, 410 +/- 37 msec; SCL, 426 +/- 34 msec) than in group I (CSNRT, 717 +/- 52 msec, P < 0.005; SCL, 568 +/- 73 msec, P < 0.05). Both IF and AT of the SN were greater in group I (IF, 9.7 +/- 1.9%; AT, 32.6 +/- 5.9%) than in seven sham dogs (IF, 2.4 +/- 0.9%, P < 0.05; AT, 4.0 +/- 1.7%, P < 0.05) and in group II dogs (IF, 4.0 +/- 2.0%, P < 0.05; AT, 4.0 +/- 1.7%, P < 0.05). End-labeling assay was positive in three of nine dogs in group I, but negative in group II and sham dogs. CONCLUSIONS: Rapid atrial pacing impaired SN function through IF and AT of the SN. Enalapril prevented these pacing-induced degenerative changes and improved SN function.

Analysis of Variance↗
PubMed2005

Dynamic changes in the QT-R-R relationship during head-up tilt test in patients with vasovagal syncope.

BACKGROUND: QT interval is influenced by preceding R-R intervals and autonomic nervous tone. Changes in QT intervals during vasovagal reflex might reflect autonomic modulation of ventricular repolarization; however, this issue has not been fully elucidated. This study aimed to evaluate dynamic response of QT interval to transient changes in R-R interval during vasovagal syncope (VVS) induced by head-up tilt test. METHODS: Eighteen patients with VVS and 18 age-and sex-matched controls were studied. All patients with VVS had a positive mixed-type response to head-up tilt and all controls had a negative response. CM5-lead digital electrocardiogram (ECG) was recorded and QT intervals were analyzed using Holter ECG analyzer. Using scatter plots of consecutive QT and the preceding R-R intervals, QT-R-R relations during tilt-up and tilt-back or during vasovagal reflex were independently fitted to an exponential curve: QT (second) = A + B x exp[k x R-R (second)]. RESULTS: During the tilt-up, A, B, and k did not differ between patients with VVS and controls. During the tilt back, k showed equivalent positive value compared to the tilt-up (4.1 +/- 1.3 vs -4.6 +/- 0.9) in controls. However, k remained negative (-1.3 +/- 1.5) during vasovagal reflex in patients with VVS. In six patients, in whom metoprolol was effective in eliminating VVS, QT-R-R relationship during the tilt-back became similar to that in controls. CONCLUSIONS: In patients with VVS, hysteresis of the QT-R-R relation is similarly shown during tilt-up as in controls, whereas this hysteresis is no longer evident and failure of QT prolongation is observed during VVS.

Adrenergic beta-Antagonists↗
PubMed2005

Identification of a novel splice site mutation of the CSPG2 gene in a Japanese family with Wagner syndrome.

PURPOSE: To investigate the genetic basis and clinical variability of Wagner syndrome, a rare, dominantly inherited vitreoretinopathy. METHODS: Clinical examination, linkage analysis, and mutational screening were performed in a large, three-generation, consanguineous Japanese family with Wagner syndrome. The effect of splice site mutation was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis with lymphoblastoid cell total RNAs generated from affected individuals. RESULTS: Ocular phenotypes of affected members included an empty vitreous with fibrillary condensations, avascular membrane, perivascular sheathing, and progressive chorioretinal dystrophy and were similar to those of the original Wagner syndrome family. All affected eyes examined exhibited pseudoexotropia with ectopic fovea. No systemic manifestations were observed. Genetic linkage confirmed disease segregation with the previously identified WGN1 locus on 5q13-q14. A heterozygous A-->G transversion at the second base of the 3'-acceptor splice site of intron 7 (c.4004-2 A-->G) of the chondroitin sulfate proteoglycan 2 (CSPG2) gene that cosegregated with the disease was identified. Results of RT-PCR analysis indicated that the c.4004-2 A-->G mutation activates a cryptic splice site, located 39 bp downstream from the authentic 3' splice acceptor site. CONCLUSIONS: This linkage study confirmed the genetic homogeneity of the Wagner syndrome. CSPG2 encodes versican, a large chondroitin sulfate proteoglycan, which, in vitreous, binds to hyaluronan and link protein and forms large aggregates that are important for maintaining structural integrity. Although the CSPG2 gene has been excluded as a candidate for causing Wagner syndrome, these data emphasize the necessity of further mutational screening in new families and careful functional characterization.

Adolescent↗
PubMed2005

PKClambda regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic beta cells.

Altered regulation of insulin secretion by glucose is characteristic of individuals with type 2 diabetes mellitus, although the mechanisms that underlie this change remain unclear. We have now generated mice that lack the lambda isoform of PKC in pancreatic beta cells (betaPKClambda(-/-) mice) and show that these animals manifest impaired glucose tolerance and hypoinsulinemia. Furthermore, insulin secretion in response to high concentrations of glucose was impaired, whereas the basal rate of insulin release was increased, in islets isolated from betaPKClambda(-/-) mice. Neither the beta cell mass nor the islet insulin content of betaPKClambda(-/-) mice differed from that of control mice, however. The abundance of mRNAs for Glut2 and HNF3beta was reduced in islets of betaPKClambda(-/-) mice, and the expression of genes regulated by HNF3beta was also affected (that of Sur1 and Kir6.2 genes was reduced, whereas that of hexokinase 1 and hexokinase 2 genes was increased). Normalization of HNF3beta expression by infection of islets from betaPKClambda(-/-) mice with an adenoviral vector significantly reversed the defect in glucose-stimulated insulin secretion. These results indicate that PKClambda plays a prominent role in regulation of glucose-induced insulin secretion by modulating the expression of genes important for beta cell function.

Animals↗
PubMed2005

Effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers.

This study was performed to investigate the effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers. Five or 10 mg of carvedilol was orally administered to 23 subjects (22-44 years old), and blood samples were taken at 2 and 6 h after dosing. We determined the polymorphic alleles of CYP2D6 in each subject. The whole blood concentration of R- and S-carvedilol was measured by an HPLC method. The pharmacokinetic parameters in individual subjects were estimated by the Bayesian method using the nonlinear mixed effects model (NONMEM) program. The mean values of oral clearance for R- and S-carvedilol were estimated to be 1.01 and 2.15 l/h/kg, respectively. The oral clearance was highly correlated with the apparent volume of distribution among the subjects, suggesting that the interindividual difference in bioavailability was largely responsible for the pharmacokinetic variability of carvedilol. The oral clearance and also volume of distribution of both enantiomers were significantly lower in the subjects with the CYP2D6*10 allele than with the CYP2D6*1/*1 or *1/*2 genotype. These results suggested that the systemic and/or pre-systemic metabolism of R- and S-carvedilol in the liver is significantly decreased in Japanese with the CYP2D6*10 allele.

Adult↗
PubMed2005

Pharmacokinetic variability of routinely administered bisoprolol in middle-aged and elderly Japanese patients.

The nonlinear mixed effects model (NONMEM) was used to analyze the pharmacokinetics of routinely administered bisoprolol in middle-aged and elderly Japanese patients. The subjects consisted of 29 males and 11 females with a mean age of 63.5+/-10.1. Data on the plasma concentration of bisoprolol from 94 blood samples obtained at steady-state following repetitive oral administration were analyzed using the NONMEM program, where a one-compartment model with repetitive bolus dosing was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F). Individual CL/F values were correlated with body weight (WT) and creatinine clearance (CLcr). The relation between CLcr and the CL/F of bisoprolol was not altered by the CYP2D6 and CYP2C19 genotypes, gender, or age. The mean CL/F value estimated with NONMEM was 0.0612.WT+1.15.CLcr (l/h), and the mean V/F value was 2.61.WT (l). The residual interindividual variability of CL/F and V/F were 22.0% and 12.6%, respectively. The pharmacokinetic variability of bisoprolol is small even in routinely treated Japanese patients, provided that both body weight and renal function are taken into account for the prediction of oral clearance of the drug.

Adult↗
PubMed2005

Central sympathetic inhibition augments sleep-related ultradian rhythm of parasympathetic tone in patients with chronic heart failure.

BACKGROUND: Abnormal sleep dynamics in patients with heart failure is one of the mechanisms for the relative predominance of central sympathetic outflow over parasympathetic tone. This study was designed to examine whether central sympathoinhibition could improve the sympathovagal imbalance related to rapid-eye-movement (REM)/non-REM ultradian sleep rhythm in these patients. METHODS AND RESULTS: Beat-by-beat RR intervals of overnight electrocardiogram were serially subject to power spectral analysis in 14 patients with chronic heart failure and 13 age-matched subjects with normal cardiac function. To assess autonomic sleep dynamics, the ultradian rhythm was extracted from all-night consecutive high-frequency (HF) components of heart rate variability (HRV) before and after administration of an (alpha2)-adrenergic agonist, guanfacine. Night-time HRV in heart failure was characterized by an attenuated ultradian rhythm of HF-components with a concomitant reduction in averaged HF power. Guanfacine reduced blood pressure, heart rate, and plasma norepinephrine concentrations by 7%, 8%, and 34% (p < 0.01), respectively. After guanfacine, HF power rose by 154% (p < 0.01) with a prominent augmentation of the all-night ultradian rhythm (+361%, p < 0.01). CONCLUSIONS: Central sympathoinhibition augments a sleep-related ultradian rhythm of parasympathetic tone, suggesting a potential benefit to autonomic balancing and sleep quality in patients with chronic heart failure.

Adult↗
PubMed2005

Ischemia-induced norepinephrine release, but not norepinephrine-derived free radicals, contributes to myocardial ischemia-reperfusion injury.

BACKGROUND: Norepinephrine (NE)-derived free radicals may contribute to myocyte injury after ischemia -reperfusion, so the influence of sympathetic denervation on myocardial ischemia - reperfusion injury was investigated in the present study. METHODS AND RESULTS: Cardiac sympathetic denervation was produced in Wistar rats by a solution of 10% phenol 1 week before ischemia. Atenolol (0.5 mg/kg) was intravenously administered 10 min before the coronary occlusion. The left coronary artery was occluded for 30 min and thereafter reperfused. Cardiac interstitial fluid was collected by a microdialysis probe and free radicals in dialysate were determined by electron paramagnetic resonance (EPR) spin trapping, using 5,5-dimethyl-1-pyrroline-N-oxide as a spin trap. The ratio of infarct size to the ischemic area at risk (I/R) was decreased in both the phenol and atenolol groups compared with control (28.5+/-11.3, 31.8+/-10.7 vs 50.6+/-14.7%, p<0.05). During the coronary occlusion, concentrations of interstitial NE increased markedly in the control and atenolol groups, but was unchanged in the phenol group. EPR signal intensity (relative value to internal standard) was maximal at 1 h after reperfusion and was similar in the phenol and control groups (0.32+/-0.15 vs 0.45+/-0.19). CONCLUSIONS: Cardiac denervation protected myocyte against ischemia-reperfusion injury through decreasing direct NE toxicity, but not through decreasing NE-derived free radicals.

Animals↗
PubMed2005

Augmented ciliary reorientation response and cAMP-dependent protein phosphorylation induced by glycerol in triton-extracted Paramecium.

In the presence of 30% glycerol, the cilia of a permeabilized cell model from Paramecium exhibit dynamic orientation changes while displaying only a restricted cyclic beating with a very small amplitude. The direction of cilia under these conditions corresponds to the direction of the effective power stroke of cilia beating in the absence of glycerol, i.e., pointing posteriorly in the absence of Ca2+ and anteriorly at > 10(-6) M Ca2+. Ciliary reorientation toward the posterior in response to the removal of Ca2+ is particularly conspicuous; all the cilia become predominantly pointing to the posterior end all through their beating phases. Previous studies suggested that the effect of glycerol is caused through modification of cAMP-dependent protein phosphorylation. To determine whether glycerol in fact affects ciliary reorientation through changes in protein phosphorylation, here we examined protein phosphorylation in the axonemes. Glycerol stimulated cAMP-induced phosphorylation of 29-kDa and 65-kDa proteins. The stimulation of phosphorylation was found to be partly due to the inhibition of endogenous phosphodiesterase (PDE), and partly due to the inhibition of the dephosphorylation of the 29-kDa and 65-kDa phosphoproteins within the axoneme. Thus glycerol appears to cause predominant posterior orientation of cilia by stimulating cAMP-dependent phosphorylation on those proteins. In addition, glycerol appears to inhibit ciliary beating through inhibition of dynein ATPase.

Animals↗
PubMed2005

Inappropriate secretion of antidiuretic hormone in a patient with chronic inflammatory demyelinating polyneuropathy.

A 54-year-old man suffered from a relapse of chronic inflammatory demyelinating polyneuropathy (CIDP), and developed quadriplegia and somnolence requiring mechanical ventilation for respiratory failure. Serum Na concentration remained at low levels during the clinical course, and a diagnosis of inappropriate secretion of antidiuretic hormone (SIADH) was made. The present case had not only acute aggravation of CIDP with autonomic dysfunction but also intracranial hypertension caused by increased CSF protein (maximum level, 1,315 mg/dl). It seemed likely that injury of the afferent fibers of the baroregulatory pathway or intracranial hypertension might have contributed to SIADH in this patient.

Humans↗