HIGHLY SELECTIVE SIGMA-RECEPTOR LIGANDS ELEVATE INOSITOL 1,4,5-TRISPHOSPHATE PRODUCTION IN RAT CARDIAC MYOCYTES

Exposure of cardiac myocytes from adult rat ventricles to the highly s elective, high affinity sigma receptor ligands R-cis-N-[2-(3,4-dichlor ophenyl)ethyl]-N-methyl-2-( 1-pyrrolidinyl)-cyclohexylamine (BD-737) ( 0.1-100 nM) and hlorophenyl)ethyl]N,N',N'-trimethylethylenediamine (BD -1047) (0.01-10 nM), caused potentiation of electrically-evoked amplit udes of contraction and Ca2+ transients, while exposure to 100 nM ED-1 047 caused attenuation of these amplitudes. In addition, BD-737 (0.1-1 00 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 whic h deplete the sarcoplasmic reticulum Ca2+ stores. Inositol 1,4,5-trisp hosphate (IP3) production in cardiac myocytes was determined by the IF , binding protein assay. Both substances caused an increase in the int racellular concentration of IP3. BD-737 caused a rapid transient incre ase to 3.2-fold in 1 min and stabilization at 2.1-fold of control ther eafter. ED-1047 caused a gradual increase reaching 4.4-fold after 5 mi n. The results suggest that the effects of these sigma receptor ligand s on contractility and spontaneous contractions are mediated by activa tion of phospholipase C and elevation of intracellular IP3 level. (C) 1998 Elsevier Science B.V. All rights reserved.