Stobadine is a potent modulator of endogenous endothelin-1 in human fibroblasts.
Binding of endothelin (ET) peptides to their respective receptors with resulting proliferation of vascular smooth muscle has been implicated in the pathogenesis of arterial hypertension and atherosclerosis. Recently it was hypothesized that endothelin- (ET-1) bound to its two membrane receptors (ET(A) and ET(B)) continues to activate signal transducing proteins in cells. It was also shown that pyridoindole stobadine stabilized lysosomal membranes in myocardium in early ischemia. Therefore we decided to study the effects of stobadine on specific, subtype-selective binding and subsequent degradation of human, synthetic [125I]-ET-1 in human fibroblasts (HF). Our results indicate that stobadine significantly potentiated ET-1 binding by reductive ET(B) selective degradation of ET-1 in HF. Hence, it is very plausible that stobadine may modulate endogenous endothelin and its intracellular mitogenic and chemotactic factors, principally by affecting two presumably related processes, participating in the proliferative and mitogenic response, (1) potentiation of signal trasduction from ET(A) receptors, and (2) subtype-ET(B) selective intracellular processing.
Drimal
J
J
Slovak Academy of Sciences, Bratislava, Slovak Republic.
Patoprsty
V
V
Kovacik
V
V
D000975:Antioxidants / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology*; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D016232:Endothelins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D008934:Mitogens / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism
D000975:Antioxidants; D001381:Azepines; D002243:Carbolines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D007457:Iodine Radioisotopes; D008934:Mitogens; D009842:Oligopeptides; D010446:Peptide Fragments; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C075771:BQ 3020; C087850:PD 151242; D002738:Chloroquine; C100106:dicarbine