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SK&F 96365, a novel inhibitor of receptor-mediated calcium entry.

Publication ,  Journal Article
Merritt, JE; Armstrong, WP; Benham, CD; Hallam, TJ; Jacob, R; Jaxa-Chamiec, A; Leigh, BK; McCarthy, SA; Moores, KE; Rink, TJ
Published in: Biochem J
October 15, 1990

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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Published In

Biochem J

DOI

ISSN

0264-6021

Publication Date

October 15, 1990

Volume

271

Issue

2

Start / End Page

515 / 522

Location

England

Related Subject Headings

  • Umbilical Veins
  • Rabbits
  • Platelet Aggregation Inhibitors
  • Neutrophils
  • Manganese
  • Ion Channel Gating
  • Imidazoles
  • Humans
  • Fura-2
  • Fluorescent Dyes
 

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Merritt, J. E., Armstrong, W. P., Benham, C. D., Hallam, T. J., Jacob, R., Jaxa-Chamiec, A., … Rink, T. J. (1990). SK&F 96365, a novel inhibitor of receptor-mediated calcium entry. Biochem J, 271(2), 515–522. https://doi.org/10.1042/bj2710515
Merritt, J. E., W. P. Armstrong, C. D. Benham, T. J. Hallam, R. Jacob, A. Jaxa-Chamiec, B. K. Leigh, S. A. McCarthy, K. E. Moores, and T. J. Rink. “SK&F 96365, a novel inhibitor of receptor-mediated calcium entry.Biochem J 271, no. 2 (October 15, 1990): 515–22. https://doi.org/10.1042/bj2710515.
Merritt JE, Armstrong WP, Benham CD, Hallam TJ, Jacob R, Jaxa-Chamiec A, et al. SK&F 96365, a novel inhibitor of receptor-mediated calcium entry. Biochem J. 1990 Oct 15;271(2):515–22.
Merritt, J. E., et al. “SK&F 96365, a novel inhibitor of receptor-mediated calcium entry.Biochem J, vol. 271, no. 2, Oct. 1990, pp. 515–22. Pubmed, doi:10.1042/bj2710515.
Merritt JE, Armstrong WP, Benham CD, Hallam TJ, Jacob R, Jaxa-Chamiec A, Leigh BK, McCarthy SA, Moores KE, Rink TJ. SK&F 96365, a novel inhibitor of receptor-mediated calcium entry. Biochem J. 1990 Oct 15;271(2):515–522.
Journal cover image

Published In

Biochem J

DOI

ISSN

0264-6021

Publication Date

October 15, 1990

Volume

271

Issue

2

Start / End Page

515 / 522

Location

England

Related Subject Headings

  • Umbilical Veins
  • Rabbits
  • Platelet Aggregation Inhibitors
  • Neutrophils
  • Manganese
  • Ion Channel Gating
  • Imidazoles
  • Humans
  • Fura-2
  • Fluorescent Dyes