Manidipine inhibits endothelin-1-induced [Ca2+]i signaling but potentiates endothelin's effect on c-fos and c-jun induction in vascular smooth muscle and glomerular mesangial cells.
We studied the effects of manidipine, a newly synthesized dihydropyridine Ca2+ channel antagonist, on endothelin-1 (ET-1)-induced [Ca2+]i signaling and immediate-early gene induction in vascular smooth muscle A7r5 cells and glomerular mesangial cells (MCs). ET-1-induced a dose-dependent, biphasic increase in [Ca2+]i in both A7r5 cells and MCs. Manidipine inhibited the ET-1-induced [Ca2+]i increase by reducing both the transient and sustained Ca2+ increments in A7r5 cells and MCs. At concentrations of 10(-10) to 10(-6) mol/L, inhibition was dose dependent with a median effective dose (ED50) of 10(-9) mol/L. A 20-minute preincubation period was required to observe the maximal inhibitory effect of manidipine. In contrast, manidipine (10(-5) mol/L) potentiated ET-1-induced c-fos and c-jun expression in A7r5 cells. This potentiating effect appeared 30 minutes after manidipine was added to the media and lasted for 15 hours. Manidipine alone had no detectable effect on c-fos steady-state messenger ribonucleic acid level. Manidipine induced c-jun expression starting at 60 minutes but with much lower potency. These data demonstrate that manidipine is a potent inhibitor for ET-1-induced [Ca2+]i signaling and that manidipine has multiple effects on ET-1-induced signaling, including potentiating the immediate-early gene response.
Department of Medicine, University Hospitals of Cleveland, OH 44106.
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S
Huang
M S
MS
Simonson
M J
MJ
Dunn
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009578:Nitrobenzenes; D010879:Piperazines; D011519:Proto-Oncogenes / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D016232:Endothelins; D009578:Nitrobenzenes; D010879:Piperazines; C054218:manidipine; D002118:Calcium