Biomedical subjects

T Tateishi

Publications and source records attributed to T Tateishi.

At least 55 records · Page 3Linked to original sources

PubMed1999

Real time observation of platelet adhesion to opaque biomaterial surfaces under shear flow conditions.

We developed a new system which enables direct observation of platelet adhesion on opaque biomaterials under shear flow conditions, by combining a thin quartz cone which produces laminar shear flows, with an upright epifluorescence microscope which visualizes stained platelets through the rotating cone. This is the first report on the observation of platelets adhered to opaque biomaterials in real time under shear flow conditions. The direct observation of platelet adhesion to expanded polytetrafluoroethylene (ePTFE) as an opaque biomaterial revealed that the kinetics of platelet adhesion to ePTFE depended greatly on shear stresses, showing that the shear stress of 5.0 dyne/cm2 induced higher adhesiveness of platelets to ePTFE than that of either 0.1 or 15 dyne/cm2. The observation also showed a difference in platelet adhesiveness among ePTFEs with different fibril lengths--0, 3.2, 18, and 35 microm--indicating that ePTFEs with shorter fibril length had lower adhesiveness of platelets under a shear stress of 5.0 dyne/cm2. It is indispensable for analyzing the phenomena of platelet adhesion to opaque biomaterials to observe in real-time rolling, adhesion, and detachment of platelets under shear stresses without disturbing shear flow conditions. The results showed that the mechanical and optical design of the system could serve this purpose.

Algorithms↗

PubMed1999

Effects of nitric oxide synthase inhibitor on tyrosine hydroxylase mRNA in the adrenal medulla of spontaneously hypertensive and Wistar Kyoto rats.

We studied the effects of N(G)-nitro-l-arginine methyl ester (L-NAME) on catecholamine levels, tyrosine hydroxylase (TH) activity, and TH mRNA levels in the adrenal medulla of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). L-NAME (100 mg/L in drinking water) and atropine (10 mg/L in drinking water) were administered for 2 weeks. Epinephrine and norepinephrine levels, TH activity, and TH mRNA levels in the adrenal medulla of L-NAME-treated WKY were significantly decreased. These parameters were not significantly altered in the adrenal medulla of L-NAME-treated SHR. Nitrite/nitrate levels in the adrenal medulla of L-NAME-treated WKY were significantly decreased; however, no significant change in L-NAME-treated SHR was observed. Ca(2+)-dependent nitric oxide synthase (NOS) activity in the adrenal medulla of SHR was significantly decreased compared to that of WKY. TH mRNA levels in L-NAME + atropine-treated and L-NAME-treated WKY were significantly lower than TH mRNA levels in control WKY. These results suggest that nitric oxide in the adrenal medulla may enhance the catecholamine biosynthetic pathway via increased TH mRNA expression. Our results also suggest that this effect is suppressed in SHR due to decreased NOS activity in the adrenal medulla.

Adrenal Medulla↗

PubMed1999

Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation capacity in a Japanese population.

OBJECTIVE: To analyze the CYP2D6 allele frequencies in a Japanese population and to evaluate the effects of CYP2D6 variants on in vivo CYP2D6 activity as measured by the dextromethorphan metabolic ratio (MR). METHODS: Ninety-eight unrelated, healthy Japanese men were phenotyped with dextromethorphan and genotyped by the polymerase chain reaction amplification method for 7 CYP2D6 alleles. RESULTS: The CYP2D6*1, CYP2D6*10, CYP2D6*2, CYP2D6*5, CYP2D6*4, and CYP2D6*21 allele frequencies in our Japanese subjects were 0.423, 0.408, 0.092, 0.061, 0.020, and 0.010, respectively. Thirty-three subjects (33.7%) were heterozygous for *10/*1, and 18 (18.4%) and 17 (17.3%) subjects were homozygous for *1 and *10, respectively. Subjects who were homozygous for *10 showed the highest dextromethorphan MR among these 3 genotypes. Eighteen subjects (18.3%) were heterozygous for *2, but their dextromethorphan MR values were not greater than the MR values of subjects who were homozygous for *1. One subject was a poor metabolizer phenotypically, and he was homozygous for *5. CONCLUSIONS: The CYP2D6 allele frequencies in our Japanese subjects differed from those determined in previous studies of white subjects or mainland Chinese subjects. Individuals homozygous for *10 who have relatively low in vivo CYP2D6 activity represent almost 20% of the Japanese population. In addition, we did not identify any subjects with amplified *2 among our 98 Japanese men.

Adult↗

PubMed1999

Ursodeoxycholic acid prevents hepatic cytochrome P450 isozyme reduction in rats with deoxycholic acid-induced liver injury.

BACKGROUND/AIMS: Hydrophobic bile acids, such as deoxycholic acid produce cholestatic liver injury. Ursodeoxycholic acid has been shown to be useful in the treatment of cholestatic liver disease. METHODS: In this study, we investigated the effects of deoxycholic acid or ursodeoxycholic acid (1% of diet, for 14 days) and their combination (1% each) on expression of hepatic cytochrome P450 isozymes, their related enzyme activities and mRNA level in rats. RESULTS: Adding 1% deoxycholic acid to chow caused a marked increase in serum total bilirubin (47-fold) and total bile acid (8-fold) concentrations and in alkaline phosphatase (2.5-fold, p<0.01) and alanine aminotransferase activities (23.5-fold, p<0.01). Adding the same dose of ursodeoxycholic acid along with the deoxycholic acid mitigated both the rise in serum total bilirubin and bile acid concentrations and that in alkaline phosphatase and alanine aminotransferase activities, although the use of ursodeoxycholic acid alone did not affect any of the above. Feeding 1% deoxycholic acid caused a decrease (48% of control) in total cytochrome P450 content in hepatic microsomes. Addition of 1% ursodeoxycholic acid along with the 1% deoxycholic acid completely prevented the decrease in total cytochrome P450 content. Feeding ursodeoxycholic acid alone did not affect the total cytochrome P450 content. The expression of cytochrome P450 2B1, 2E1, 3A2, 2C6, 2C11 and 4A1 proteins in hepatic microsomes was decreased by deoxycholic acid (44, 51, 23, 59, 30 and 74% of control, respectively). Likewise, the activities of cytochrome P450 2B1 (pentoxyresorufin O-depentylation), 2E1 (aniline p-hydroxylation) and 3A2 (testosterone 6beta-hydroxylation) isozymes and the 3A2 mRNA levels in liver were decreased by deoxycholic acid. Addition of 1% ursodeoxycholic acid to 1% deoxycholic acid also prevented the decrease in these cytochrome P450 proteins, related enzyme activities and mRNA levels in liver. CONCLUSIONS: These results indicate that, in rats with deoxycholic acid-induced liver injury, ursodeoxycholic acid prevents the decrease in hepatic cytochrome P450 isozymes and suggest that ursodeoxycholic acid is useful for the treatment of liver injury in terms of aiding the normalization of the hepatic drug-metabolizing system.

Animals↗

PubMed1999

Laparoscopic ultrasonography versus operative cholangiography during laparoscopic cholecystectomy: review of the literature and a comparison with open intraoperative ultrasonography.

BACKGROUND: Laparoscopic ultrasonography (LUS) has been used increasingly over the last several years as a new imaging modality. To define the role of LUS during laparoscopic cholecystectomy, we evaluated LUS by prospectively comparing it with operative cholangiography (OC), by reviewing the literature on LUS, and by retrospectively comparing it with intraoperative ultrasonography performed during open cholecystectomy. STUDY DESIGN: LUS and OC were compared prospectively in 100 consecutive patients during laparoscopic cholecystectomy. The success rate of examination, the time required, the accuracy in diagnosing bile duct calculi, and the delineation of biliary anatomy were evaluated. RESULTS: The success rate of examination was 95% for LUS and 92% for OC. The main reason for unsatisfactory LUS was incomplete visualization of the distal common bile duct. The time required was 8.2 minutes for LUS and 15.9 minutes for OC (p<0.0001). Nine patients had bile duct calculi. LUS had one false-negative result and OC had two false-positives and one false-negative. The accuracies of LUS and OC were comparable except for a slightly better positive predictive value of LUS (100% versus 77.8%; p>0.1). In a literature review, 12 recent prospective studies comparing LUS and OC and three studies on open intraoperative ultrasonography were reviewed. Twelve studies of LUS with a total of 2,059 patients demonstrated results similar to the present study. The success rate was 88% to 100% for both tests. The time for LUS was approximately 7 minutes, about half of the time needed for OC. Overall, LUS was associated with fewer false-positive results than OC; the positive predictive value and specificity of LUS were better, while the sensitivity and negative predictive value of LUS and OC were comparable. OC detected ductal variations or anomalies more distinctly than LUS. Compared with open intraoperative ultrasonography, LUS had a slightly lower success rate and required a slightly longer time because it was technically more demanding, but the two procedures had a similar accuracy for diagnosing bile duct calculi. CONCLUSIONS: Because of their different advantages and disadvantages, LUS and OC can be used in a complementary manner. There is a learning curve for LUS because of its technical difficulty. Once learned, however, LUS can be used as the primary screening procedure for bile duct calculi because of its safety, speed, and cost-effectiveness. OC can be used selectively, particularly when ductal anatomic variations or anomalies or bile duct injuries are suspected.

Cholangiography↗

PubMed1999

Ticlopidine decreases the in vivo activity of CYP2C19 as measured by omeprazole metabolism.

AIMS: To examine the effect of ticlopidine administration on the activities CYP2C19 and CYP3 A in vivo using omeprazole as a model substrate. METHODS: A single dose of 40 mg omeprazole was administered orally with or without ticlopidine (300 mg daily for 6 days) to six Japanese extensive metabolisers with respect to CYP2C19. Blood samples were taken for the measurement of plasma concentrations of omeprazole, 5-hydroxyomeprazole and omeprazole sulphone. RESULTS: Ticlopidine administration increased omeprazole Cmax (1978+/-859/ 3442+/-569 (control phase/ticlopidine phase, nm )) and decreased the oral clearance of omeprazole (CL/F; 25.70+/-16. 17/10.76+/-1.16 (control phase/ticlopidine phase, l h-1 )) significantly. The 5-hydroxyomeprazole to omeprazole AUC ratio (0. 817+/-0.448/0.236+/-0.053 (control phase/ticlopidine phase)) and the 5-hydroxyomeprazole to omeprazole sulphone AUC ratio (1.114+/-0. 782/0.256+/-0.051 (control phase/ticlopidine phase)) were decreased significantly after ticlopidine administration. The decrease in omeprazole CL/F and the 5-hydroxyomeprazole to omeprazole AUC ratio correlated significantly with their respective absolute values when the drug was given alone. The decrease in CL/F following ticlopidine administration correlated with that in the 5-hydroxyomeprazole to omeprazole AUC ratio. CONCLUSIONS: These findings suggest that ticlopidine inhibited the in vivo activity of CYP2C19, but not, or to a lesser extent CYP3 A4, and that the magnitude of inhibition by ticlopidine is related to the in vivo activity of CYP2C19 before inhibition.

Adult↗

PubMed1999

Role of CYP3A in bromperidol metabolism in rat in vitro and in vivo.

1. The aim was to identify whether CYP3A metabolizes bromperidol (BP), an antipsychotic drug, to form 4-fluorobenzoyl-propionic acid (FBPA) in hepatic microsomes from 8-week-old male Sprague-Dawley rats and to investigate whether an inhibitor or an inducer of CYP3A affects BP pharmacokinetics in rat. 2. In an in vitro study, only troleandomycin showed marked inhibition of FBPA formation among several specific CYP isozyme inhibitors studied including troleandomycin, diethyldithiocarbamate, furafylline and quinine. Anti-rat CYP3A2 serum inhibited FBPA formation by 80%, whereas other anti-rat CYP sera (1A1, 1A2, 2B1, 2C11, 2E1) only slightly inhibited it. 3. In a pharmacokinetic study, BP half-life was prolonged to 137% of the average control value by 7-day treatment with erythromycin, a CYP3A inhibitor, and shortened to 58% of the control by 2-day treatment with dexamethasone, a CYP3A inducer. BP clearance was reduced to 68% of the control by erythromycin and was increased to 145% of control by dexamethasone. 4. These results suggested that BP biotransformation is catalysed mainly by CYP3A to form FBPA in rat and that the modification of this enzyme activity would affect the pharmacokinetics of BP.

Animals↗

PubMed1999

Effects of hyperbaric oxygen on procollagen messenger RNA levels and collagen synthesis in the healing of rat tendon laceration.

In the present study, we examined the effect of intermittent exposure to hyperbaric oxygen (HBO) on experimentally induced tendon laceration in the right hind limb of 56 male Wistar rats. We compared animals treated by HBO (2 atmospheres absolute [ATA] 100% O(2) x 60 min x once per day) with control animals (without HBO) at 3, 7, 14, and 28 days after wound creation. Histology, and pro-alpha1 (I) mRNA by Northern hybridization, pro-alpha1 (III) mRNA, transforming growth factor-beta1 (TGF-beta1) mRNA by RT-PCR were studied. Our results indicate the use of HBO influences the pro-a1 (I) mRNA expression. The level of pro-alpha1 (I) mRNA was especially increased at 7 14 days after laceration by HBO. These results suggest that intermittent oxygen exposure may play a significant role in collagen synthesis and be beneficial for producing the extracellular matrices in tissue engineering.

Animals↗

PubMed1999

Role of CYP3A in haloperidol N-dealkylation and pharmacokinetics in rats.

Haloperidol (HP), an antipsychotic drug, is N-dealkylated by cytochrome P450 (CYP) to 4-fluorobenzoylpropionic acid (FBPA). The purpose of this study was to identify whether CYP3A metabolizes HP to FBPA in hepatic microsomes of rats and to investigate whether an inhibitor or an inducer of CYP3A affects HP pharmacokinetics in rats. The rate of FBPA formation was determined in hepatic microsomes from 8-week-old male Sprague-Dawley rats. Among several specific CYP isozyme inhibitors including troleandomycin (TAO), diethyldithiocarbamate, furafylline and quinine, only TAO showed marked inhibition of FBPA formation. Anti-rat CYP3A serum inhibited FBPA formation by 76.4%, while other anti-rat CYP sera (1A1, 1A2, 2B1, 2C11, 2E1) only slightly did. In a pharmacokinetic study, 8-week-old male Sprague-Dawley rats were given 0.5 mg/kg HP intravenously after treatment with 100 mg/kg erythromycin, a CYP3A inhibitor, or 80 mg/kg dexamethasone, a CYP3A inducer, intraperitoneally once a day for 7 days or 2 days, respectively or untreated. HP half-life was prolongated to 171% of the average control value by erythromycin and shortened to 49% of control by dexamethasone. HP clearance was reduced to 63% of control by erythromycin and was increased to 167% of control by dexamethasone. These results suggested that CYP3A mainly catalyzed HP to FBPA in rats, and the modification of this enzyme activity would affect the pharmacokinetics of HP.

Animals↗

PubMed1999

A comparison of the effect of five phenothiazines on hepatic CYP isoenzymes in rats.

We examined the influence of five phenothiazine derivatives on the activity and the expression of hepatic cytochrome P450 (CYP) 1A, 2B, 2C6, 2C11, 2E1 and 3A2 in male Sprague-Dawley rats. Twenty mg/kg of phenothiazine, chlorpromazine, and thioridazine, or 1 mg/kg of trifluoperazine and perphenazine was administered intraperitoneally for 4 consecutive days. Phenothiazine increased the total CYP content and induced CYP1A, CYP2B, and CYP3A. Western blot analysis showed marked induction of CYP1A1 by phenothiazine. Chlorpromazine induced CYP2B, and CYP3A without a significant increase in the CYP content. Thioridazine decreased the total CYP content and reduced CYP2C11, CYP2E1, and CYP3A. Neither trifluoperazine nor perphenazine significantly altered the catalytic activity or the protein level of any enzyme examined. These results suggest that the antipsychotic phenothiazine derivatives examined here hardly affect CYP1A at the pharmacological doses, while phenothiazine does induce it. Although a relatively short period and small dose of administration might counteract the influence, trifluoperazine and perphenazine have less effect on CYP subfamilies than chlorpromazine or thioridazine.

Animals↗

PubMed1999

Induction of hepatic CYP2B in foetal and neonatal rats after maternal administration of phenobarbital.

We examined hepatic cytochrome P450 (CYP) induction in rat foetuses and neonates by phenobarbital administered through placenta or breast feeding. In an intraperitoneal study, phenobarbital was administered intraperitoneally to mother rats once a day for 7 consecutive days before delivery. The livers were removed from foetuses, neonates, and mothers just before and 5 and 10 days after delivery. In oral administration study, water containing phenobarbital was given orally ad libitum from day 13 of pregnancy to 3 weeks after delivery (end of lactation). The livers were removed from neonates and mothers just before and one week after delactation. Phenobarbital administered intraperitoneally increased both the activity and the protein expression of CYP2B in 5-day-old neonates, even though the administration ended before delivery. This increase had disappeared in 10-day-old neonates. In mother rats, phenobarbital increased CYP2B just before and 5 days after delivery, while no increase was detected 10 days after delivery. Phenobarbital administered orally also increased both the activity and the protein expression of CYP2B of neonates and mothers during lactation and this increase also disappeared 1 week after delactation. Neither activity nor protein expression of CYP3A were induced in perinates at any age examined in either administration route. In mother rats, increase in CYP3A was found only just before delivery in the peritoneal administration study. Our results suggest that phenobarbital administered through placenta or breast milk transiently induces hepatic CYP2B in newborn rats but that the influence of phenobarbital does not last long.

Administration, Oral↗

PubMed1999

Developmental changes in urinary elimination of theophylline and its metabolites in pediatric patients.

We investigated the developmental changes in the pattern of urinary metabolites of theophylline, a substrate for CYP1A2, to study when CYP1A2, which is absent in the perinatal period, fully develops during childhood. The urinary ratios of three metabolites (1-methyluric acid, 3-methylxanthine, and 1,3-dimethyluric acid) to theophylline in patients over 3 y of age show a much larger interindividual variation compared with those under 3 y of age, and the mean values of the ratios in patients over 3 y of age were greater than those in patients under 1 y of age. The urinary ratio of 1,3-dimethyluric acid (a metabolite generated by several cytochrome P450s) to 3-methylxanthine or 1-methyluric acid (metabolites generated by CYP1A2 exclusively) seemed to be relatively constant over 3 y of age; in patients under 3 y of age, these ratios were much higher than those in patients over 3 y of age. The urinary ratio of 1-methyluric acid to 3-methylxanthine or 3-methylxanthine to 1-methyluric acid seemed to be relatively invariable in all patients except those less than 1 y of age. These findings suggest that CYP1A2 activity may be programmed to mature by around 3 y of age and that CYP1A2 probably plays a major role in theophylline 8-hydroxylation at a therapeutic concentration after the full development of CYP1A2 activity.

Aging↗

PubMed1999

Increase of hematopoietic responses by triple or single helical conformer of an antitumor (1-->3)-beta-D-glucan preparation, Sonifilan, in cyclophosphamide-induced leukopenic mice.

It has been suggested that the immunopharmacological activity of soluble (1-->3)-beta-D-glucan depends on its conformation in mice. In this study, we examined the relationship between the conformation of Sonifilan (SPG) and hematopietic responses in cyclophosphamide (Cy)-induced leukopenic mice. SPG, a high molecular weight (1-->3)-beta-D-glucan, has a triple helical conformation in water, and it was changed by treatment with aqueous sodium hydroxide to the single helical conformer (SPG-OH). The effects of SPG or SPG-OH on hematopoietic responses in cyclophosphamide induced leukopenic mice were investigated by monitoring i) gene expression of cytokines by RT-PCR, ii) protein synthesis of interleukin 6 (IL-6) by ELISA and iii) colony formation of bone marrow cells (BMC). The mice administered Cy and SPG or SPG-OH expressed and produced higher levels of IL-6 mRNA and protein than the mice administered only Cy. Gene expression of NK1.1 was also induced by Cy/SPG (or SPG-OH) treatment. Induced gene expression of stem cell factor (SCF) and macrophage-colony stimulating factor (M-CSF) by SPG/SPG-OH were also found in in vitro culture of BMC from Cy treated mice. These results strongly suggested that conformation of the glucans, single and triple helix, are independent of the hematopietic response.

Animals↗

PubMed1999

In vitro B-mode ultrasonographic criteria for diagnosing axillary lymph node metastasis of breast cancer.

Axillary lymph node status is an important factor for staging and treatment planning in breast cancer. Our study was performed in vitro on a node-by-node basis to evaluate the ability of B-mode ultrasonographic images to distinguish metastatic from nonmetastatic nodes. Immediately prior to histologic examination, individual dissected axillary nodes were scanned in a water bath using a 10 MHz B-mode ultrasonographic transducer. Four B-mode features (size, circularity, border demarcation, and internal echo) were evaluated for their ability to distinguish metastatic from nonmetastatic lymph nodes. Lymph node metastasis was indicated by (1) a large size (i.e., a length of the longest axis of 10 mm or greater); (2) a circular shape (i.e., the ratio of the shortest axis to the longest axis between 0.5 and 1.0); (3) a sharply demarcated border compared with surrounding fatty tissue; and (4) a hypoechoic internal echo, with obliteration of the fatty hilum. The sensitivity and specificity were compared for all combinations of features. We examined 84 histologically characterized axillary nodes from 27 breast cancer patients, including 64 nonmetastatic and 20 metastatic nodes. Of the criteria cited, circular shape was the best single feature for distinguishing metastatic from nonmetastatic nodes (sensitivity, 65%; specificity, 73%). The best combination of sensitivity (85%) and specificity (73%) was obtained using the criterion that a lymph node contained cancer when at least three positive features were present. The present in vitro study demonstrated that the sensitivity and specificity of B-mode ultrasonography for diagnosing lymph node metastasis were lower than 90%. Therefore, B-mode ultrasonography may not be an optimal noninvasive screening method for diagnosing axillary lymph node metastasis in breast cancer patients, particularly under in vivo clinical conditions.

Adult↗

PubMed1999

Dihydropyrimidine dehydrogenase activity and fluorouracil pharmacokinetics with liver damage induced by bile duct ligation in rats.

Hepatic metabolism is the main determinant in the pharmacokinetics of 5-fluorouracil (5-FU). Its disposition might be affected with liver dysfunction. In the present study, the influence of liver damage induced by bile duct ligation on dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in 5-FU catabolism, CYP2B, and 5-FU pharmacokinetics were compared in male Sprague-Dawley rats. After 3 weeks of the ligation in two different groups of animals for in vitro and pharmacokinetic experiments, significant increases in serum bilirubin level and spleen weight were found in both groups. No significant differences were noted in bilirubin level or spleen weight of the bile duct ligation group between the two experiment groups. In the in vitro experiment, DPD activity and protein levels determined by Western blot analysis in the bile duct ligation group were slightly but significantly greater than those of a sham-operated group, whereas CYP2B activity and protein level were significantly reduced. These findings were supported by mRNA levels of CYP2B and DPD. When 40 mg/kg 5-FU was administered i.v. in the pharmacokinetic experiment, no significant differences in pharmacokinetic parameters were found between the bile duct ligation and sham-operated groups. These results suggested that DPD activity and protein level were maintained and that 5-FU pharmacokinetics was not altered in the presence of liver damage accompanied by a significant reduction in CYP2B activity and protein level, supporting previous clinical studies showing that mild to moderate liver dysfunction does not affect 5-FU disposition.

Animals↗

PubMed1999

Evaluation of cytotoxicity of UHMWPE wear debris.

We established a novel method to investigate the phagocytosis of ultra high molecular weight polyethylene using primary macrophage cells by an inverted cell culture method. Abundant wear debris derived from implant materials are generated in aseptic loosening and are deposited in periprosthetic tissues in which they are phagocytized by mono- and multi-nucleated macrophage like cells. Ultra-high-molecular-weight-polyethylene wear debris generated from different sources namely, from laboratory test wear machine, in vivo methods and from knee and hip simulator were mainly used in this investigation. The cytotoxicity index of the different UHMWPE particles obtained from various sources were compared with that of the PE beads and the control without particles by Alamar Blue and Neutral Red assays. The results showed that the cytotoxicity index was significantly lower for the wear debris from the in vivo experiments than that for other particles. SEM analysis were also done to understand the morphology of the wear debris and polyethylene beads and to confirm the phagocytosis process. The mean diameter of the wear debris obtained from the in vivo experiments as estimated from the imaging analysis of the SEM photographs was found to be the least. The inverted cell culture method may be regarded as one of the good methods to study the phagocytosis of UHMWPE by macrophage cells.

Animals↗

PubMed1998

Effects of anti-androgen treatment on the catecholamine synthetic pathway in the adrenal medulla of spontaneously hypertensive rats.

We investigated the effects of the antiandrogen flutamide on the activity of tyrosine hydroxylase, the levels of its encoding mRNA, and catecholamine levels in the adrenal medulla of male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Flutamide (30 mg/kg) was administered subcutaneously daily (between 9 and 15 weeks of age). The systolic blood pressure of flutamide-treated SHR rats was lower than that of control SHR. Epinephrine and norepinephrine levels, tyrosine hydroxylase activity, and the levels of encoding mRNA in the adrenal medulla were significantly lower in flutamide-treated SHR rats than in paired controls. Systolic blood pressure, epinephrine and norepinephrine levels, tyrosine hydroxylase activity, and encoding mRNA in the adrenal medulla of WKY rats showed no significant differences between flutamide-treated and control groups. These findings suggested that flutamide may have cardiovascular effects through alteration of the catecholamine synthetic pathway caused by removal of androgen receptor stimulation on the expression of tyrosine hydroxylase in the adrenal medulla of male SHR rats.

Actins↗

PubMed1998

Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats.

We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t(1/2)) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t(1/2) of the dexamethasone pretreatment group (14.4+/-0.7 min) was significantly shorter than that of the prednisolone group (20.9+/-1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.

Adjuvants, Anesthesia↗