In this study, the effects of carbachol (CCh) on twitch tension, intracellular Na+ activity (aiNa), and action potential were simultaneously measured in canine cardiac Purkinje fibers in order to examine the regulation of inotropy through muscarinic receptors and its relation to aiNa. In fibers driven at 1 Hz, CCh (10 microM) initially and transiently decreased and then increased the twitch tension by 36 +/- 8%. The action potential showed a significant elevation of the plateau and a significant shortening of the duration at 90% repolarization (APD90), from 403 +/- 7 to 389 +/- 7 ms. The aiNa decreased from 7.4 +/- 0.4 to 6.7 +/- 0.3 mM (n = 23, p < 0.05). Atropine (1 microM) decreased the twitch tension by 21 +/- 6% (n = 7, p < 0.05) without significant effects on the action potential and aiNa, and inhibited the effects of CCh. Cs+ (20 mM) increased the plateau height and APD90, enhanced the twitch tension by 66 +/- 24%, but decreased aiNa from 7.3 +/- 0.3 to 6.3 +/- 0.4 mM (n = 6, p < 0.05). In the presence of 20 mM Cs+, some fibers generated slow responses. The addition of 10 microM CCh further increased the twitch tension and APD90, and decreased aiNa from 6.3 +/- 0.4 to 5.3 +/- 0.3 mM. Ouabain (0.3 microM) increased the twitch tension and aiNa, and inhibited the CCh-induced decrease of aiNa. In the presence of ouabain, 20 mM Cs+ depolarized the fiber and generated slow responses with a decreased aiNa. The addition of 10 microM CCh enhanced the slow action potential, and increased aiNa although there was a transient decrease during early exposure. These results suggest that activation of muscarinic receptors in canine Purkinje fibers results in an enhancement of the Na+-K+ pump activity and a biphasic inotropic response, probably via different receptor subtypes. The inhibitory effect, most likely through M2 receptors, is associated with the activation of K+ channels. The stimulatory effect, on the other hand, is probably due to the action on the M1 receptors, resulting in increases in Ca2+ currents.

Action Potentials↗

PubMedDate not supplied

Disposition of ethmozine in cerebrospinal fluid and plasma of rabbits.

The concentration-time profiles of ethmozine, a newly introduced anti-arrhythmic drug, in the cerebrospinal fluid (CSF) and plasma of six rabbits (New Zealand white rabbits of both sexes, 4.0-5.0 Kg) were studied after intravenous bolus administration. CSF samples at various intervals were obtained while the animal was lightly anaesthetized with intravenous thiopentone (40 mg Kg-1) and blood samples at other intervals were taken while the animal was conscious. Blood samples (1 ml) were collected from the implanted cannula of the ear artery while CSF samples (0.3 ml) were obtained from the cisterna magna. The plasma concentrations of ethmozine in six rabbits declined rapidly after intravenous injection for up to 30 min. then slowly over 12 h. Using non-compartmental analysis, the mean (+/- S.E.M.) elimination half-life, mean residence time, plasma clearance and volume of distribution at steady state were 13.9 +/- 9.2 h, 19.9 +/- 13.4 h, 2.3 Lh-1 and 26.8 +/- 7.9 L respectively. The mean CSF-plasma concentration ratios for ethmozine at 0.5, 1.0, 2.0, 4.0, 8.0 and 12.0 h were 0.17, 0.14, 0.16, 0.16, 0.23 and 0.22 respectively. The results suggest that ethmozine is able to penetrate into the CSF from the general circulation and this may be related to its adverse effects on the central nervous system.

Animals↗

PubMedDate not supplied

Deciduoid peritoneal mesothelioma: CT findings with pathologic correlation.

We report a rare case of deciduoid peritoneal mesothelioma in a 47-year-old woman who had no history of asbestos exposure or previous surgery. Immunohistochemistry and electron microscopic findings showed that the tumor was a subtype of epithelioid mesothelioma. Awareness of this disease entity is helpful for the differential diagnosis of peritoneal masses.

Female↗

PubMedDate not supplied

Reversal of multidrug resistance to epirubicin by cyclosporin A in liposomes or intralipid.

Clinical applications of the first-generation multidrug resistance (MDR) modulators, such as cyclosporin A (CsA) have been hampered because of their severe side effects in vivo. In this study, we utilized liposomes and Intralipid to provide selective delivery of CsA to tumor cells as well as to circumvent toxicities associated with CsA by altering the pharmacodistribution properties of encapsulated CsA. The MDR reversing effect of CsA in free, liposomal or Intralipid formulations on the uptake and transport of epirubicin in Caco-2 cells and rat intestines was evaluated. The results showed that CsA in free or liposomal formulations significantly enhanced the intracellular accumulation of epirubicin in a dose-related fashion in Caco-2 cells, with the highest enhancement at 2 microM: These formulations substantially ameliorated the apical to basolateral absorption of epirubicin in Caco-2 cells and markedly increased mucosal to serosal absorption of epirubicin in rat jejunum and ileum. CsA in free, liposomal or Intralipid formulations all significantly reduced basolateral to apical efflux of epirubicin across Caco-2 monolayers. CsA encapsulated in liposomes showed greater enhancement than other formulations. In conclusion, liposomal preparations of CsA may circumvent MDR and have the advantage of diminishing side effects, thus providing a useful alternative dosage form for intravenous administration of CsA to be combined with cytotoxic agents for the treatment of resistant tumors.

Adenocarcinoma↗

PubMedDate not supplied

[Removal of the 3'- and 5'-untranslated region amplifies expression of the erythropoietin gene in mammalian cells].

The effect of the 5T- and 3T-untranslated regions (UTR) of human erythropoietin gene (gEpo) on its expression in mammalian cells was investigated. 5T-UTR-deleted, 3T-UTR-deleted, and 5T,3T-UTR-deleted gEpos were transfected into COS-7 cells, and the amount of transiently expressed Epo was measured. Cells transfected with the 5T,3T-UTR-deleted gEpo showed the highest expression, 2.6 times that with wild-type gEpo. Northern blot analysis indicated that the enhanced expression of 5T,3T-UTR-deleted gEpo might be related with the transcription efficiency.

3' Untranslated Regions↗

PubMedDate not supplied

Isolation and characterization of sulphoxidation metabolites of moricizine in rat and human biological fluids.

The sulphoxidation metabolites of moricizine, moricizine sulphoxide (M-sulphoxide) and moricizine sulphone (M-sulphone) were isolated and identified in the rat bile and urine and in human plasma and urine following administration of moricizine hydrochloride. The sulphoxide and sulphone were synthesized chemically by peroxidation of moricizine hydrochloride with hydrogen peroxide at 25 degree C and 60 degree C, respectively, and were characterized by melting point determination (MP), infrared spectroscopy (IR), mass spectroscopy (MS), thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). In the rats (n=7), which were kept in metabolic cages and given intravenous moricizine (0.72 mg), the mean +/- SD percentages recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.11 +/- 0.09%, 0.74 +/- 0.45% and 5.16 +/- 4.24%, respectively. The corresponding recoveries in the bile were 0.13 +/- 0.04% as moricizine, 3.39 +/- 1.62% as M-sulphoxide and 2.16 +/- 1.07% as M-sulphone. After an oral dose of moricizine HCl (300 mg) the plasma concentrations of moricizine, M-sulphoxide and M-sulphone at 4 h in two healthy subjects were 0.43, 0.11 and 0.10 microg/ml and 0.32, 0.17 and 0.27 microg/ml, respectively for Subject 1 and Subject 2. The percentages of dose recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.14 and 0.02%, 0.27 and 0.36%, and 0.30 and 0.24%, respectively for Subject 1 and Subject 2. It is suggested that an investigation of the disposition of moricizine and its sulphoxidation metabolites in patients will be valuable for elucidating the prolonged effects in the treatment of ventricular arrhythmias.

Adult↗