Signal transduction and Ca2+ uptake activated by endothelins in rat brain endothelial cells.
The activation of signal transduction pathways by endothelin-1 or endothelin-3 were investigated in rat cerebromicrovascular endothelial cells. Endothelin-1 induced a rapid increase in inositol triphosphate (IP3) formation in these cells, whereas endothelin-3 was only moderately effective at high concentrations. Both endothelins also increased uptake of 45Ca2+ in these cells. Endothelin-1-induced IP3 formation or 45Ca2+ uptake were inhibited by endothelin ETA receptor antagonist BQ-123. Ryanodine, an inhibitor of intracellular Ca2+ mobilization, selectively endothelin-1-induced 45Ca2+ uptake, whereas nickel or suramin inhibited endothelin-3-induced 45Ca2+ uptake. The results indicate that endothelin-1 elevates 45Ca2+ uptake in rat brain endothelial cells by mechanisms coupled to the mobilization of intracellular Ca2+ stores. Both endothelin-1- and endothelin-3-induced 45Ca2+ uptake were inhibited by receptor operated Ca2+ channel blocker SK&F 96365, whereas they were insensitive to dihydropyridine derivatives nifedipine and nitrendipine. The release of arachidonic acid from rat brain endothelial cells observed in response to endothelin-1 was inhibited by ryanodine or SK&F 96365, implicating participation of both intra- and extra- cellular components of Ca2+ signaling in activating endothelial secretion of vasoactive substances.
Stanimirovic
D B
DB
Stroke Branch, NINDS, NIH, Bethesda, MD 20892.
Nikodijevic
B
B
Nikodijevic-Kedeva
D
D
McCarron
R M
RM
Spatz
M
M
D000704:Analysis of Variance; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D008833:Microcirculation; D009543:Nifedipine / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007093:Imidazoles; D010456:Peptides, Cyclic; D012433:Ryanodine; D016718:Arachidonic Acid; D015544:Inositol 1,4,5-Trisphosphate; D009568:Nitrendipine; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium