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

• Published in: European journal of pharmacology 1998-07, Vol.353 (2), p.315-327
• Main Authors: Novakova, Marie, Ela, Catherine, Bowen, Wayne D, Hasin, Yonathan, Eilam, Yael
• Format: Article
• Language: English
• Subjects: Analgesics - pharmacology; Animals; Biological and medical sciences; Ca 2+, cytosolic; Calcium - metabolism; Cardiac myocyte; Contractility; Cyclohexylamines - pharmacology; Cytosol - drug effects; Cytosol - metabolism; Ethylenediamines - pharmacology; Fundamental and applied biological sciences. Psychology; Heart; Heart Ventricles - cytology; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Inositol 1,4,5-trisphosphate; Inositol 1,4,5-Trisphosphate - biosynthesis; Ligands; Myocardial Contraction - drug effects; Phospholipase C; Pyrrolidines - pharmacology; Rats; Receptors, sigma - agonists; Receptors, sigma - metabolism; Vertebrates: cardiovascular system; σ Receptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(98)00398-7

Exposure of cardiac myocytes from adult rat ventricles to the highly selective, high affinity σ receptor ligands 1 S,2 R- 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 Ca 2+ 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 Ca 2+ stores. Inositol 1,4,5-trisphosphate (IP 3) production in cardiac myocytes was determined by the IP 3 binding protein assay. Both substances caused an increase in the intracellular concentration of IP 3. 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 IP 3 level.