Sigma receptor ligands modulate contractility, Ca++ influx and beating rate in cultured cardiac myocytes.
Specific binding of [3H]-1,3-di-o-tolylguanidine (DTG) and (+)-[3H]-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] to membranes of cultured cardiac myocytes from neonatal rats revealed the presence of sigma 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 increased (3-10 min) and finally decreased to about 75% of control level. Fluorescence measurements on indo-1 loaded cardiomyocytes revealed drug-induced changes in the size of the concentration of free cytosolic calcium ([Ca++]i)-transients, similar to the changes observed in ASM. These changes appear to be mediated by corresponding changes in the rates of 45Ca++ influx which increased 2 to 7 min after the addition of (+)-3-PPP and decrease to 50% of the control level thereafter. Preincubation with thapsigargin, which depletes the sarcoplasmic reticulum-Ca++ stores, did not affect the pattern of changes in ASM, induced by the subsequent addition of (+)-3-PPP. This indicates that the changes in [Ca++]i are not mediated by sarcoplasmic reticulum-Ca++ transport systems. Exposure to sigma ligands did not affect the apparent sensitivity of the myofilaments to Ca++, as indicated by the relationships between changes in ASM and in [Ca++]i-transients. Cultures which were not paced, contracted spontaneously at a constant rhythm. Sigma receptor ligands caused changes in beating frequencies which were followed by irregular contractions.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Bacteriology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
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Ela
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Barg
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Vogel
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Hasin
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Eilam
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000502:physiology; D006146:Guanidines / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D010423:Pentazocine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017480:Receptors, sigma / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D006146:Guanidines; D010880:Piperidines; D017480:Receptors, sigma; C026539:preclamol; D019204:GTP-Binding Proteins; D006220:Haloperidol; C050232:1,3-ditolylguanidine; D010423:Pentazocine; D002118:Calcium