| Simvastatin releases Ca2+ from a thapsigargin-sensitive pool and inhibits InsP3-dependent Ca2+ mobilization in vascular smooth muscle cells. | |
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MedLine Citation:
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PMID: 8907800 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Simvastatin (SV), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity inhibits migration and proliferation of vascular smooth muscle cells (SMC). To investigate whether these effects of SV are related to inhibition of cell calcium mobilization, cultured SMC obtained from rat aorta were loaded with Fura-2 to determine the basal cytosolic free calcium levels ([Ca2+]i) and the agonist-stimulated Ca2+ mobilization. SV (20 mu M) transiently increased cytosolic free calcium, an effect that depends mainly on intracellular calcium release (68%). This effect of SV was markedly reduced (75%) by thapsigargin, an inhibitor of the Ca2+ ATPase of inositol 1,4,5-triphosphate (InsP3)-sensitive calcium pools. Incubation of cells with SV (15 min) inhibited the mobilization of Ca2+ by angiotensin II, platelet-derived growth factor, and vasopressin (IC50 = 5 mu M). SV did not affect inositol trisphosphate (InsP3) levels or modify its generation by angiotensin II (Ang II) and vasopressin. Furthermore, in saponin-permeabilized cells, SV abolished the release of calcium by 2,3-dideoxy-InsP3. SV reduced the effect of thapsigargin on InsP3-sensitive stores by 67%, suggesting that SV depletes these calcium pools. The inhibitory effect of SV on calcium mobilization was prevented by coincubation of cultured cells (24 h) with 1 mM mevalonic acid, the product of HMG-CoA reductase activity. These results support the notion that SV inhibits [corrected] the migration and proliferation of SMC by directly affecting cell Ca2+. |
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Authors:
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N Escobales; M Castro; P I Altieri; P Sanabria |
Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of cardiovascular pharmacology Volume: 27 ISSN: 0160-2446 ISO Abbreviation: J. Cardiovasc. Pharmacol. Publication Date: 1996 Mar |
Date Detail:
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Created Date: 1997-03-13 Completed Date: 1997-03-13 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 383-91 Citation Subset: IM |
Affiliation:
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Department of Physiology, University of Puerto Rico Medical School, San Juan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Angiotensin II
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pharmacology Animals Calcium / metabolism* Calcium-Transporting ATPases / antagonists & inhibitors* Cells, Cultured Enzyme Inhibitors / pharmacology* Hydroxymethylglutaryl-CoA Reductase Inhibitors* Inositol 1,4,5-Trisphosphate / physiology* Lovastatin / analogs & derivatives*, pharmacology Muscle, Smooth, Vascular / drug effects*, metabolism Rats Simvastatin Thapsigargin / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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NIH-GM-08224/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 11128-99-7/Angiotensin II; 67526-95-8/Thapsigargin; 7440-70-2/Calcium; 75330-75-5/Lovastatin; 79902-63-9/Simvastatin; 85166-31-0/Inositol 1,4,5-Trisphosphate; EC 3.6.1.8/Calcium-Transporting ATPases |
| Comments/Corrections | |
Erratum In:
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J Cardiovasc Pharmacol 1996 Aug;28(2):344 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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