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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
1990-12-5
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pubmed:abstractText |
A novel inhibitor of receptor-mediated calcium entry (RMCE) is described. SK&F 96365 (1-(beta-[3-(4-methoxy-phenyl)propoxy]-4-methoxyphenethyl)-1H- imidazole hydrochloride) is structurally distinct from the known 'calcium antagonists' and shows selectivity in blocking RMCE compared with receptor-mediated internal Ca2+ release. Human platelets, neutrophils and endothelial cells were loaded with the fluorescent Ca2(+)-indicator dyes quin2 or fura-2, in order to measure Ca2+ or Mn2+ entry through RMCE as well as Ca2+ release from internal stores. The IC50 (concn. producing 50% inhibition) for inhibition of RMCE by SK&F 96365 in platelets stimulated with ADP or thrombin was 8.5 microM or 11.7 microM respectively; these concentrations of SK&F 96365 did not affect internal Ca2+ release. Similar effects of SK&F 96365 were observed in suspensions of neutrophils and in single endothelial cells. SK&F 96365 also inhibited agonist-stimulated Mn2+ entry in platelets and neutrophils. The effects of SK&F 96365 were independent of cell type and of agonist, as would be expected for a compound that modulates post-receptor events. Voltage-gated Ca2+ entry in fura-2-loaded GH3 (pituitary) cells and rabbit ear-artery smooth-muscle cells held under voltage-clamp was also inhibited by SK&F 96365; however, the ATP-gated Ca2(+)-permeable channel of rabbit ear-artery smooth-muscle cells was unaffected by SK&F 96365. Thus SK&F 96365 (unlike the 'organic Ca2+ antagonists') shows no selectivity between voltage-gated Ca2+ entry and RMCE, although the lack of effect on ATP-gated channels indicates that it discriminates between different types of RMCE. The effects of SK&F 96365 on functional responses of cells thought to be dependent on Ca2+ entry via RMCE were also studied. Under conditions where platelet aggregation is dependent on stimulated Ca2+ entry via RMCE, the response was blocked by SK&F 96365 with an IC50 of 15.9 microM, which is similar to the IC50 of 8-12 microM observed for inhibition of RMCE. Adhesion and chemotaxis of neutrophils were also inhibited by SK&F 96365. SK&F 96365 is a useful tool to distinguish RMCE from internal Ca2+ release, and to probe the role of RMCE in mediating functional responses of cells. However, SK&F 96365 is not as potent (IC50 around 10 microM) or selective (also inhibits voltage-gated Ca2+ entry) as would be desirable, so caution must be exercised when using this compound.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-1102606,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2109601,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2306207,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2348402,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2408921,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2439921,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2442017,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2469159,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2469160,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2536184,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2536366,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2542801,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2556820,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2730577,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2855354,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-2906130,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-3094510,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-3325037,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-3412458,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-3492515,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-3838314,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-4897900,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-686171,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2173565-7063049
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1-(2-(3-(4-methoxyphenyl)propoxy)-4-...,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Diphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Aminoquinolines,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channel Blockers,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channels,
http://linkedlifedata.com/resource/pubmed/chemical/Fluorescent Dyes,
http://linkedlifedata.com/resource/pubmed/chemical/Fura-2,
http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Manganese,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Aggregation Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Quin2
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0264-6021
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
271
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
515-22
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:2173565-Adenosine Diphosphate,
pubmed-meshheading:2173565-Adenosine Triphosphate,
pubmed-meshheading:2173565-Aminoquinolines,
pubmed-meshheading:2173565-Animals,
pubmed-meshheading:2173565-Blood Platelets,
pubmed-meshheading:2173565-Calcium,
pubmed-meshheading:2173565-Calcium Channel Blockers,
pubmed-meshheading:2173565-Calcium Channels,
pubmed-meshheading:2173565-Cell Adhesion,
pubmed-meshheading:2173565-Chemotaxis, Leukocyte,
pubmed-meshheading:2173565-Endothelium, Vascular,
pubmed-meshheading:2173565-Fluorescent Dyes,
pubmed-meshheading:2173565-Fura-2,
pubmed-meshheading:2173565-Humans,
pubmed-meshheading:2173565-Imidazoles,
pubmed-meshheading:2173565-Ion Channel Gating,
pubmed-meshheading:2173565-Manganese,
pubmed-meshheading:2173565-Neutrophils,
pubmed-meshheading:2173565-Platelet Aggregation Inhibitors,
pubmed-meshheading:2173565-Rabbits,
pubmed-meshheading:2173565-Umbilical Veins
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pubmed:year |
1990
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pubmed:articleTitle |
SK&F 96365, a novel inhibitor of receptor-mediated calcium entry.
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pubmed:affiliation |
SmithKline Beecham Pharmaceuticals, Frythe, Welwyn, Herts, U.K.
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pubmed:publicationType |
Journal Article
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