title: Highly selective sigma receptor ligands elevate inositol 1,4,5-trisphosphate production in rat cardiac myocytes.
abstract: Exposure of cardiac myocytes from adult rat ventricles to the highly selective, high affinity sigma receptor ligands 1S,2 R-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)-cycloh exylamine (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 sigma receptor ligands on contractility and spontaneous contractions are mediated by activation of phospholipase C and elevation of intracellular IP3 level.
authors.affiliation: Department of Bacteriology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Novakova
authors.forename: C
authors.initials: C
authors.lastname: Ela
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
authors.forename: Y
authors.initials: Y
authors.lastname: Hasin
authors.forename: Y
authors.initials: Y
authors.lastname: Eilam
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003514:Cyclohexylamines / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005029:Ethylenediamines / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D008024:Ligands; D009200:Myocardial Contraction / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism
chemical_list: D000700:Analgesics; D003514:Cyclohexylamines; D005029:Ethylenediamines; D008024:Ligands; D011759:Pyrrolidines; D017480:Receptors, sigma; C075567:BD 737; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium