Document Detail


Simvastatin releases Ca2+ from a thapsigargin-sensitive pool and inhibits InsP3-dependent Ca2+ mobilization in vascular smooth muscle cells.
MedLine Citation:
PMID:  8907800     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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+.
Authors:
N Escobales; M Castro; P I Altieri; P Sanabria
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  27     ISSN:  0160-2446     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  1996 Mar 
Date Detail:
Created Date:  1997-03-13     Completed Date:  1997-03-13     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  383-91     Citation Subset:  IM    
Affiliation:
Department of Physiology, University of Puerto Rico Medical School, San Juan.
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II / 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:
NIH-GM-08224/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
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:
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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