SIGMA-RECEPTOR LIGANDS MODULATE CONTRACTILITY, CA++ INFLUX AND BEATING RATE IN CULTURED CARDIAC MYOCYTES

Specific binding of [H-3]-1,3-di-o-tolylguanidine (DTG) and +)-[H-3]-( 3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] to membranes of c ultured cardiac myocytes from neonatal rats revealed the presence of s igma receptors on these cells. Exposure of cultured cardiomyocytes to nanomolar concentrations of (+)3-PPP, (+)-pentazocine and haloperidol induced specific patterns of changes in contractility of electrically paced cultures. The amplitude of systolic cell-motion (ASM) decreased by 10 to 25% 1 to 2 min after drug addition, then transiently increase d (3-10 min) and finally decreased to about 75% of control level. Fluo rescence measurements on indo-1 loaded cardiomyocytes revealed drug-in duced changes in the size of the concentration of free cytosolic calci um ([Ca++](i))-transients, similar to the changes observed in ASM. The se changes appear to be mediated by corresponding changes in the rates of Ca-45(++) influx which increased 2 to 7 min after the addition of (+)-3-PPP and decrease to 50% of the control level thereafter. Preincu bation with thapsigargin, which depletes the sarcoplasmic reticulum-Ca ++ stores, did not affect the pattern of changes in ASM, induced by th e subsequent addition of (+)-3-PPP. This indicates that the changes in [Ca++](i) are not mediated by sarcoplasmic reticulum-Ca++ transport s ystems. Exposure to sigma ligands did not affect the apparent sensitiv ity of the myofilaments to Ca++, as indicated by the relationships bet ween changes in ASM and in [Ca++](i)-transients. Cultures which were n ot paced, contracted spontaneously at a constant rhythm. Sigma recepto r ligands caused changes in beating frequencies which were followed by irregular contractions. The present work suggests that sigma receptor s may have an important role in regulating contractility, beating rate s and Ca++ fluxes in cardiac myocytes.