Effects of amiodarone and bepridil on ventricular depolarization and repolarization.
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Amiodarone↗
Biomedical subjects
H Honjo
Publications and source records attributed to H Honjo.
Contribution of aromatase to the deoxyribonucleic acid synthesis of MCF-7 human breast cancer cells and its suppression by aromatase inhibitors.
We have studied the effects of various steroids on DNA synthesis in MCF-7 human breast carcinoma cells, which have aromatase activity and which exert an oestrogen receptor-mediated growth, to assess the significance of intracellular aromatase on growth stimulation as well as inhibition by aromatase inhibitors. The cells were cultured for 96 h in phenol red-free medium containing 10% charcoal-treated fetal bovine serum and test reagents and pulse-labelled with [3H]thymidine. Physiological concentrations of oestradiol, oestrone, testosterone (T) and androstenedione (AD) stimulated thymidine incorporation. However, oestrone-sulphate and dihydrotestosterone (DHT) only stimulated at concentrations greater than the physiological levels. T and DHT stimulation was blocked by tamoxifen, but not by cyproterone acetate, suggesting that the stimulation was mediated via the oestrogen receptor but not by the androgen receptor. Stimulation by T and AD was reduced by aminoglutethimide and 14 alpha-hydroxy-4-androstene-3,6,17-trione, both of which inhibit aromatase activity, however, stimulation by nonaromatizable DHT was not reduced by the inhibitors, suggesting that androgens were converted by the intracellular aromatase to oestrogens which stimulated the thymidine incorporation. It is suggested that intracellular aromatase significantly contributes to the stimulation of DNA synthesis and that aromatase inhibitors suppress the stimulation.
Androgens↗
The physiological role of estradiol 17-sulfate during pregnancy.
To clarify the physiological role of estradiol 17-sulfate (ES) during pregnancy, experiments were conducted and the following results were obtained: (1) serum or urinary ES levels rose as a function of gestational age; (2) placental microsomes showed fairly high 2- and 4-hydroxylase activity for ES; and (3) the catechol products, 2- and 4-hydroxy-ES, had a strong inhibitory effect upon the in vitro production of lipid peroxides. These results suggest that ES acts as a precursor to the catechol metabolites which maintain normal gestation. This is coincident with the negative correlation of serum levels in ES and lipid peroxides observed in late pregnancy.
Chromatography, High Pressure Liquid↗
Estrogen as a growth factor to central nervous cells. Estrogen treatment promotes development of acetylcholinesterase-positive basal forebrain neurons transplanted in the anterior eye chamber.
In a previous report, we demonstrated in vivo ameliorating effects of conjugated estrogen in women suffering from senile dementia-Alzheimer's type. To investigate the effects of estrogen on the growth of cholinergic neurons, the present study was performed using rat cholinergic tissue implanted into the anterior chamber of the eye. Fetal diagonal band tissue containing cholinergic neurons was grafted into the anterior eye chamber of adult female rats that had either been treated or not with 2 mg estradiol valerate injected every 3 days after oophorectomy. Two and four weeks after transplantation, the axonal and/or dendritic growth of cholinergic neurons in the graft was studied using acetylcholinesterase histochemistry. At both times, acetylcholinesterase positive processes were densely distributed in the grafts of estradiol valerate treated rats, while in rats without estradiol valerate treatment acetylcholinesterase positive reaction was essentially localized only on the cell bodies. These findings were more obvious at 2 weeks after transplantation than at 4 weeks. These results suggest that estrogen acts on cholinergic neurons as a growth factor.
Acetylcholinesterase↗
A case of testicular feminization syndrome with bulimia nervosa.
A 19-year-old patient with a female appearance visited our department for treatment of bulimia nervosa. The patient had primary amenorrhea. Chromosomal studies revealed a 46XY karyotype, and the plasma testosterone level was in the range of normal adult males. The patient was diagnosed as having testicular feminization syndrome. The psychological background, such as severe anxieties concerning her body, was behind the eating disorders. Examinations revealed intraabdominal testes. A bilateral gonadectomy was performed, and no androgen receptors were detected in the suprapubic skin. After the gonadectomy, the patient's mental status became much more stable, and the ability to control her eating pattern was restored. Testicular feminization with bulimia nervosa is rare in Japan. The importance of mental support and a careful follow-up to people with testicular feminization is being discussed.
Adult↗
Electrophysiological effects of diprafenone, a dimethyl congener of propafenone on guinea-pig ventricular cells.
1. The effects of diprafenone and propafenone on transmembrane action potential were examined and compared in papillary muscles and single ventricular myocytes isolated from guinea-pig hearts. 2. In papillary muscles, both diprafenone and propafenone > or = 10(-6) M caused a significant and dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential. 3. In the presence of either drug, trains of stimuli at rates > or = 0.1 Hz led to an exponential decline in Vmax. A time constant (tau R) for Vmax recovery from the use-dependent block was 15.5 s for diprafenone and 8.8 s for propafenone. 4. The use-dependent block of Vmax with diprafenone was enhanced when the resting potential was depolarized by high (8, 10 mM) [K+]o, whereas that with propafenone was virtually unchanged. tau R with diprafenone was shortened by the depolarization, while that with propafenone was rather prolonged. 5. In single myocytes perfused with diprafenone or propafenone, 10 ms conditioning clamp to 0 mV caused a significant decrease in Vmax of subsequent action potential. A prolongation of the clamp pulse duration resulted in a modest enhancement of the Vmax inhibition with diprafenone, while a large enhancement of the Vmax inhibition occurred with propafenone. 6. These findings suggest that diprafenone, like propafenone, may block the sodium channel during both the activated and inactivated states. The relative contribution of inactivation block is less important for diprafenone than for propafenone. The different voltage-dependence of use-dependent block with diprafenone from propafenone would contribute to its high antiarrhythmic potency.
Action Potentials↗
Desensitization to acetylcholine in single sinoatrial node cells isolated from rabbit hearts.
The negative chronotropic effect of acetylcholine (ACh) on the sinoatrial node fades in the continuous presence of ACh as a result of desensitization. We have investigated the mechanism underlying desensitization in single rabbit sinoatrial node cells using the whole cell patch clamp technique. The negative chronotropic effect resulting from the injection of a constant hyperpolarizing current faded. ACh activated an inwardly rectifying potassium current (iK,ACh), which faded in the continuous presence of ACh. ACh had no effect on "basal" L-type calcium current (iCa), but ACh decreased iCa, which had been potentiated by isoprenaline. This effect did not fade during a 2-min exposure to ACh. ACh decreased the hyperpolarization-activated current (i(f)). This effect again did not fade. These results suggest that desensitization of the negative chronotropic response to ACh is, in part, the result of the membrane hyperpolarization and, in part, the result of the fade of iK,ACh. These results also suggest that, whereas the activation of potassium current by ACh rapidly fades, the effects resulting from the inhibition of adenylate cyclase do not.
Acetylcholine↗
A model analysis for competitive binding of mexiletine and aprindine to the cardiac sodium channel.
A simulation model was developed to predict complex interaction between antiarrhythmic drugs and cardiac sodium channels. This model has four assumptions: (1) Vmax of the action potential is a linear indicator of available sodium channel conductance; (2) antiarrhythmic drugs block the channel by binding to a single common receptor site associated with the channel; (3) binding and dissociation rate constants differ for the three channel states: activated, inactivated and resting, and (4) both drug-free and drug-bound channels change states far more rapidly than binding and dissociation processes. Binding and dissociation rate constants for the three channel states were calculated from single cell experiments using guinea pig hearts. Vmax changes reflecting tonic and use-dependent sodium channel block in the presence of mexiletine and aprindine were simulated and compared with those obtained in the single cell experiments. The model predicted that 'tonic' Vmax inhibition would be enhanced, whereas 'use-dependent' ones would be attenuated after admixture of mexiletine with aprindine. The mechanisms would involve competitive interaction at the common receptor site. Single-cell experiments supported this prediction. We conclude that our simple two-drug binding model provides a useful tool to predict pharmacological interaction between class I antiarrhythmic drugs given in combination.
Action Potentials↗
Serum estradiol 17-sulphate and lipid peroxides in late pregnancy.
Estradiol 17-sulphate is readily converted to 2-OH or 4-OH estradiol 17-sulphate. The latter two strongly antagonize lipid peroxidation, which may play certain roles during pregnancy, such as pregnancy-induced hypertension. Serum estradiol 17-sulphate during mid and late pregnancy was measured using a direct radioimmunoassay without hydrolysis, and the level increased as pregnancy progressed. The levels in the sixth (20-23 weeks) and tenth months (36-39 weeks) of gestation were 1.42 +/- 0.04 nmol/l (mean +/- SD) and 3.42 +/- 1.09 nmol/l, respectively. The maternal venous levels before and at delivery and in the umbilical veins and artery were 3.38 +/- 0.83, 3.48 +/- 1.53, 4.11 +/- 1.40 and 4.30 +/- 1.81 nmol/l, respectively. The latter two values were slightly higher than the former two. Estradiol 17-sulphate in maternal venous blood began to decrease around delivery. Serum lipid peroxides were measured using the method of Yagi. Estradiol 17-sulphate and lipid peroxides showed a simple regression slope (r = -0.548, p less than 0.05) during late pregnancy. These results suggest that estradiol 17-sulphate may be converted to 2-OH or 4-OH estradiol 17-sulphate, which act as lipid peroxide scavengers during pregnancy.
Estradiol↗
Homogeneous and self-similar diffusion-limited aggregation including surface-diffusion processes.
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Journal Article↗
Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional Japanese diet.
Epidemiologic studies revealed low mortality in hormone-dependent cancer in Japanese women and men consuming a traditional diet. We previously found that certain diphenolic food components, lignans and isoflavonoids, which are converted to biologically active hormone-like substances by intestinal microflora, may be cancer-protective agents. Therefore, we studied urinary excretion of these compounds (enterolactone, enterodiol, daidzein, equol, and O-desmethylangolensin) in 10 women and 9 men in a rural village south of Kyoto, Japan. The subjects consumed a typical low-fat diet with much rice and soy products, fish, and vegetables. An isotope-dilution gas chromatographic-mass spectrometric method was used for the assays. The urinary excretion of lignans was low but that of the isoflavonoids was very high. The excretion of isoflavonoids correlated with soybean-product intake. The low mortality in breast and prostate cancer of Japanese women and men, respectively, may be due to the high intake of soybean products.
Adult↗
Block of cardiac sodium channels by amiodarone studied by using Vmax of action potential in single ventricular myocytes.
1. Acute effects of amiodarone on cardiac sodium channels were investigated in ventricular myocytes isolated from guinea-pig hearts, and compared with those of lignocaine. 2. Transmembrane potential was recorded and controlled by whole-cell current-clamp and voltage-clamp respectively through suction pipette electrodes. The maximum upstroke velocity (Vmax) of the action potential was used as a qualitative index of sodium channel availability. 3. In myocytes treated with amiodarone (1 microM) or lignocaine (40 microM), Vmax of reference action potential elicited at 0.03 Hz was decreased by 6-11%, indicating minimal tonic block of sodium channels. 4. Application of a single conditioning depolarization to those myocytes resulted in a significant decrease in Vmax of a subsequent test action potential. The Vmax reduction was enhanced in a single exponential function as the clamp pulse duration was prolonged. Time constants at 0 mV clamp were 25 ms for amiodarone and 122 ms for lignocaine. 5. Vmax recovery of test action potential following a 1000 ms 0 mV clamp was approximated by a dual exponential function. Time constants for the late slow component (tau R) at the resting potential level were 418 ms for amiodarone and 178 ms for lignocaine. tau R values were shortened in a voltage-dependent manner by hyperpolarization during the coupling interval. 6. These findings suggested that amiodarone, like lignocaine, blocks the sodium channel primarily when it is in the inactivated state. Both onset and offset kinetics of the block are very rapid. Such sodium channel blocking characteristics may contribute to its potent antiarrhythmic activity.
Action Potentials↗
Antiestrogenic effect of gestrinone as an inhibitor of [3H]-estradiol binding to nuclear type II sites.
Gestrinone has a biophysical antiestrogenic effect. But the mechanism of its antiestrogenic effect is not clear. Gestrinone blocked the increase of estrogen binding of nuclear type II sites and uterine weight in the estrogen-treated immature rabbit. Competitive assays indicated that gestrinone, at low concentrations (0.4 approximately 4 nM), inhibited [3H]-estradiol binding to nuclear type II sites. This inhibitory effect was the same as the addition of 20 microM diethyl-stilbestrol. This inhibition with gestrinone on [3H]-estradiol binding to nuclear type II sites appeared only when used at concentrations less than an equivalent molar of [3H]-estradiol. Time course analysis of the gestrinone binding inhibition showed that within the first 6 min gestrinone did not inhibit specific [3H]-estradiol binding to nuclear type II sites. This gestrinone-mediated inhibition was not observed in soluble fractions such as the cytosolic and KCl-extracted nuclear binding sites. These results suggest that gestrinone acts primarily on the nuclear fraction and then it operates the inhibitory mechanism on estradiol binding to nuclear type II sites.
Animals↗
Two types of sodium channel block by class-I antiarrhythmic drugs studied by using Vmax of action potential in single ventricular myocytes.
The state-dependent sodium channel block by mexiletine, tocainide, lidocaine, OPC-88117, aprindine, quinidine, disopyramide and AN-132 was investigated in single ventricular myocytes isolated from guinea-pig hearts. A single conditioning clamp pulse with a duration from 10 ms to 1000 ms was applied from the resting potential (-82 mV) to 0 mV level using a suction pipette whole-cell voltage clamp technique, and the maximum upstroke velocity (Vmax) of a test action potential elicited 100 ms after termination of the clamp pulse was measured as an index of sodium channel availability. In myocytes treated with the eight drugs, such clamp pulse caused a significant decrease in Vmax. With mexiletine, tocainide, lidocaine, OPC-88117 and aprindine, the Vmax reduction was enhanced progressively as the clamp pulse duration was prolonged. With quinidine, disopyramide and AN-132, an appreciable Vmax reduction at the shortest clamp pulse was followed by an additional small enhancement of the Vmax decay. These findings suggest that the former group of drugs may block the sodium channel mainly during the inactivated state (inactivation blockers), whereas the latter one may do so mainly during the activated state (activation blockers). Multiple short clamp pulses caused a greater Vmax reduction than a single prolonged clamp pulse for the activation blockers, and vice-versa for the inactivation blockers. Molecular dimensions of the eight drugs, which were estimated by X-ray diffraction of crystals, did not satisfy a simple size criterion as proposed by Courtney (1988) to explain such different types of sodium channel block by Class-I drugs.
Action Potentials↗
Estrone sulfatase activity in human uterine leiomyoma.
Human uterine leiomyoma is a benign tumor and its development is closely related to estrogen. In this study, estrone sulfatase (E1SF) activity and concentrations of estrone (E1) and estrone sulfate (E1S) were measured in endometrial, leiomyoma, and myometrial tissues of the same human uterus (n = 11) with a leiomyoma. E1SF activity in endometrial tissue overlying a leiomyoma was 2.62 +/- 0.29 nmole/hr/mg protein (mean +/- SD), this activity being significantly higher (P less than 0.01) compared with that in normal endometrial tissue (2.0 +/- 0.24 nmole/hr/mg protein). E1SF activity in normal endometrial tissue was significantly higher (P less than 0.001) compared with that in leiomyoma tissue (0.49 +/- 0.82 nmole/hr/mg protein) or myometrial tissue (0.76 +/- 0.10 nmole/hr/mg protein). We also found a significant difference (P less than 0.05) in E1SF activity between leiomyoma tissue and myometrial tissue. On the other hand, the E1 concentration in endometrial tissue overlying a leiomyoma (10.9 +/- 8.9 pg/mg protein) proved to be higher than that in endometrial tissue overlying normal myometrium (1.23 +/- 1.97 pg/mg protein). E1S concentrations in these tissues, however, were 631 +/- 339 and 902 +/- 482 pg/mg protein, respectively, these values showing a trend opposite that of the E1 concentration data. Thus, these results suggest that high E1SF activity and high E1 concentration in the endometrium overlying a leiomyoma may be related to estrogen supply to a uterine leiomyoma node.
Endometrium↗
Selective aromatase inhibition by pyridoglutethimide, an analogue of aminoglutethimide.
The inhibitory effects of pyridoglutethimide (3-ethyl-3-(4-pyridyl)piperidine-2,6-dione), an analogue of aminoglutethimide, on aromatase and other cytochrome P-450-dependent steroid-metabolizing enzymes were studied in vitro. Pyridoglutethimide and aminoglutethimide showed competitive inhibition of human placental aromatase activity with apparent Ki values of 1.7 and 0.7 mumol/l, respectively. Both pyridoglutethimide and aminoglutethimide inhibited the aromatase activity of uterine leiomyoma and cultured choriocarcinoma Enami cells as well as immunopurified human placental aromatase cytochrome P-450 by more than 90%, with IC50 values of 10-19 and 5-7 mumol/l, respectively. These results might suggest that the inhibitors interacted directly with the aromatase cytochrome P-450 of these tissues. Aminoglutethimide inhibited bovine adrenal cholesterol side-chain cleavage activity with an IC50 value of 40 mumol/l and inhibited 21-hydroxylase activity slightly, but did not inhibit 17 alpha-, 11 beta- and 18-hydroxylase at concentrations up to 100 mumol/l. On the other hand, pyridoglutethimide had no inhibitory effect on any of these enzymes at concentrations up to 50 mumol/l, although it inhibited 11 beta- and 18-hydroxylase slightly at 100 mumol/l. These results indicated that pyridoglutethimide was an aromatase inhibitor of a comparable potency to aminoglutethimide, but that it did not inhibit other steroid hydroxylases.
Aminoglutethimide↗
[Study on the local estrogen biosynthesis in human uterine leiomyoma].
The growth of uterine leiomyoma is regulated not only by the estrogen levels in blood, but also by estrogen production in the tumor itself. In this study, we investigated both the estrone formation (estrone sulfatase activity) and the transformation from estrone to estrone sulfate (estrone sulfotransferase activity) in human leiomyoma tissue. We compared them with those in the myometrium and endometrial tissues overlying and opposite a uterine leiomyoma node. We also measured the tissue concentrations of estrone, estradiol and estrone sulfate. Estrone sulfatase activity in the uterine leiomyoma was 0.49 +/- 0.08 nmol/h/mg protein (Mean +/- SE), and was lower than that in the myometrial tissue (0.76 +/- 0.09). Moreover, the enzyme activity was higher in the endometrium overlying the leiomyoma node (2.62 +/- 0.29) than in the endometrium opposite to it (2.10 +/- 0.24). On the other hand, estrone sulfotransferase activity in the myoma (20.2 +/- 2.4 pmol/h/mg protein) was higher than in myometrial tissue (16.7 +/- 2.3). The concentrations of estrone and estradiol in leiomyoma tissue were lower than in the tissues surrounding the leiomyoma. The tissue concentration of estrone sulfate was higher in leiomyoma tissues. These results suggest that estrone sulfate is hydrolyzed mainly by estrone sulfatase in the endometrium and myometrium surrounding leiomyoma nodes and the estrone formed may affect the growth of leiomyoma.
Adult↗
[Quantitative evaluation of bone mineral contents of hand bone using CR technique].
We evaluated the clinical applicability of a matrix compression technique on computed radiography (CR) data for quantitative measurements of bone mineral content of hand bones. Similar results were obtained compared to those obtained by the conventional microdensitometry (MD) technique. This CR technique which uses imaging plates should take the place of the normal MD technique due to the fact that it provides for the reduction of exposure dosage.
Absorptiometry, Photon↗