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Biomedical subjects

A Mach

Publications and source records attributed to A Mach.

6 recordsLinked to original sources
PubMed1996

Epidermal growth factor promotes a cardiomyoblastic phenotype in human fetal cardiac myocytes.

Peptide growth factors likely play an important role in cardiac development, but growth factors which inhibit or prevent differentiation in cardiac myocytes are largely unknown. Using immunocytochemistry, Western and Northern blotting, and RNase protection assays, we demonstrate that epidermal growth factor (EGF) significantly inhibits differentiation and promotes proliferation in cultured human fetal ventricular cardiac myocyte cell lines. In enriched cell lines and in a pure myocyte cell strain, EGF inhibited increases in immunoreactive sarcomeric actin and sarcomeric myosin heavy chain (SMHC) normally seen after serum withdrawal. In the pure myocyte strain, EGF induced a cardiomyoblastic phenotype; i.e., it caused a complete loss of detectable sarcomeric proteins in the majority of cells; it was also mitogenic. EGF inhibited expression of cardiac alpha-actin and SMHC mRNAs, but inhibition of SMHC expression was predominantly of the beta-MHC isoform. Removal of EGF was followed by reexpression of sarcomeric proteins. Blocking the EGF receptor (EGFR) with monoclonal anti-receptor antibody completely abolished the dedifferentiating effects of EGF and also significantly reduced the mitogenic effect of the peptide. The results indicate that activation of the EGFR both inhibits differentiation and promotes proliferation of human fetal ventricular myocytes in vitro. These findings suggest an important role for EGF in human cardiac differentiation and development.

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PubMedDate not supplied

Pharmacokinetics of thioridazine and its metabolites in blood plasma and the brain of rats after acute and chronic treatment.

This study was aimed at investigation of the pharmacokinetics of thioridazine and its metabolites after a single and repeated administrations. Male Wistar rats received thioridazine as a single dose (10 mg/kg i.p.) or they were treated chronically with the neuroleptic (10 mg/kg i.p., twice a day for two weeks). Plasma and brain concentrations of thioridazine and its metabolites (N-desmethylthioridazine, mesoridazine, sulforidazine, and the ring sulfoxide) were determined using the HPLC method. The obtained data showed that sulfoxidation in position 2 of the thiomethyl substituent and in the thiazine ring are main metabolic pathways of thioridazine, and showed that, in contrast to humans, in the rat N-desmethylthioridazine is formed in appreciable amount. The biotransformation of thioridazine was rather fast yielding plasma peak concentrations of metabolites lower than that of the parent compound. The maximum concentrations of thioridazine and its metabolites in the brain appeared later than in plasma. The peak concentrations and AUC values of thioridazine and its metabolites were higher in the brain than in plasma and this corresponded well with their longer half-lives in the brain as compared to plasma. The drug was not taken up by the brain as efficiently as other phenothiazines. Chronic treatment with thioridazine produced significant increases (with the exception of thioridazine ring sulfoxide) in the plasma concentrations of the parent compound and its metabolites which was accompanied with the prolongation of their plasma half-lives. The observed plasma levels of thioridazine were within 'therapeutic range' while the concentrations of its metabolites were relatively lower as compared to those observed in psychiatric patients. The increased plasma concentrations of thioridazine and its metabolites observed in plasma after chronic treatment were not followed by parallel changes in the brain.

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