Coupling of endothelin receptors to ion channels in rat glomerular mesangial cells.
Endothelin (ET) induces depolarization and contraction of glomerular mesangial cells (MCs), thereby influencing intraglomerular hemodynamics and filtration rate. In an attempt to clarify the ionic mechanism by which ET regulates MC function, we examined, using the whole-cell configuration of the patch-clamp technique, the effects of ET-1 and its related peptides, ET-3, sarafotoxin 6c (S6c), and IRL 1620, on ion currents and membrane potential in the primary culture of rat MCs. The resting potential of MCs was -48.4 +/- 1.9 mV (n = 23). It depolarized in response to ET-1, ET-3, and IRL 1620 by 14 (n = 7), 8 (n = 5), and 13 mV (n = 9), respectively. Whole-cell recording in combination with ion substitution ascertained the coexistence of potassium (IK) and chloride (ICl) currents. ET-1 (0.01-100 nM), ET-3 (1-100 nM), IRL 1620 (0.1-100 nM), and S6c (0.01-10 nM) augmented ICl in a concentration-dependent fashion, with ET-1 and S6c being the most potent. These actions were blocked by IRL 1038, a selective ETB receptor antagonist, but not by 1 microM BQ 123 (a selective ETA receptor antagonist) or 0.1 microM nifedipine (an L-type Ca(2+)-channel blocker). These results suggest a close coupling of the ETB receptor to ICl. ET-1, IRL 1620, and SRTX-6c in a similar concentration range also caused suppression of IK. This action was partially blocked by IRL 1038 and minimally affected by BQ 123, indicating a contributory role for ETB receptors in the regulation of IK.(ABSTRACT TRUNCATED AT 250 WORDS)
Hu
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Research Department, Ciba-Geigy Corp., Summit, NJ 07901.
Kim
H S
HS
Lappe
R W
RW
Webb
R L
RL
D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism*; D014757:Viper Venoms / Q000494:pharmacology
D018118:Chloride Channels; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007473:Ion Channels; D010446:Peptide Fragments; D015221:Potassium Channels; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; C074308:sovateltide; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21)