Highly selective σ receptor ligands elevate inositol 1,4,5-trisphosphate production in rat cardiac myocytes

Marie Novakova, Catherine Ela, Wayne D. Bowen, Yonathan Hasin, Yael Eilam

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Exposure of cardiac myocytes from adult rat ventricles to the highly selective, high affinity σ receptor ligands 1S,2R-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)-cyclohexylamine (BD-737) (0.1-100 nM) and N-[2-(3,4-dichlorophenyl)ethyl]-N,N',N'-trimethylethylenediamine (BD-1047) (0.01-10 nM), caused potentiation of electrically-evoked amplitudes of contraction and Ca2+ transients, while exposure to 100 nM BD-1047 caused attenuation of these amplitudes. In addition, BD-737 (1-100 nM) and BD-1047 (10-100 nM) caused an increase in the incidence of spontaneous twitches. These effects were inhibited when the incubation with BD-737 was done in the presence of the phospholipase C inhibitor, neomycin, or after pre-incubation with thapsigargin or caffeine which deplete the sarcoplasmic reticulum Ca2+ stores. Inositol 1,4,5-trisphosphate (IP3) production in cardiac myocytes was determined by the IP3 binding protein assay. Both substances caused an increase in the intracellular concentration of IP3. BD-737 caused a rapid transient increase to 3.2-fold in 1 min and stabilization at 2.1-fold of control thereafter. BD-1047 caused a gradual increase reaching 4.4-fold after 5 min. The results suggest that the effects of these σ receptor ligands on contractility and spontaneous contractions are mediated by activation of phospholipase C and elevation of intracellular IP3 level. Copyright (C) 1998 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)315-327
Number of pages13
JournalEuropean Journal of Pharmacology
Volume353
Issue number2-3
DOIs
StatePublished - 24 Jul 1998
Externally publishedYes

Bibliographical note

Funding Information:
This research was partially supported by the Israel Science Foundation founded by The Israel Academy of Sciences and Humanities (to Y.E.), and partially supported by a grant from the Chief Scientist of the Ministry of Health, Israel (to Y.E.).

Funding

This research was partially supported by the Israel Science Foundation founded by The Israel Academy of Sciences and Humanities (to Y.E.), and partially supported by a grant from the Chief Scientist of the Ministry of Health, Israel (to Y.E.).

FundersFunder number
Israel Academy of Sciences and Humanities
Israel Science Foundation
Ministry of Health, State of Israel

    Keywords

    • Ca, cytosolic
    • Cardiac myocyte
    • Contractility
    • Inositol 1,4,5-trisphosphate
    • Phospholipase C
    • σ Receptor

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