title: The effect of opiate agonists and antagonists on Na(+)-Ca2+ exchange in cardiac sarcolemma vesicles.
abstract: Opiate agonists and antagonists inhibit Na(+)-Ca2+ exchange in the isolated cardiac sarcolemma vesicles. Non-opioid stereoisomers (dextrorphan, Mr 1542MS, WIN 44,441-3) display effects similar to their opioid isomers (levorphanol, Mr 1543MS, WIN 44,441-2) suggesting that inhibition is not mediated by opiate receptors. Naloxone (permeable) and methylnaloxone (impermeable) inhibit the Na(+)-Ca2+ exchange similarly, suggesting an extravesicular location of inhibitory site. The inhibitory potency of naloxone is pH-independent in the range of 7.4-9.1, suggesting that the charge-carrying properties of drug-protein interactions are not altered under the tested conditions. Opiates display similar dose-response relationships for Na(+)-Ca2+ exchange and its partial reaction, the Ca(2+)-Ca2+ exchange. The opiate-induced inhibition is complete and noncompetitive in regard to extravesicular calcium. These data suggest that opiates do not bind to the Ca(2+)-binding domain (A-site), but they may interest either with the Na(+)-binding site (B-site) or with a putative opiate-binding site, presumably located outside of the ion-binding vicinity. Further studies on structure-activity relationship might lead to the discovery of potent and more specific inhibitors of cardiac Na(+)-Ca2+ exchanger. A possible relevance of these findings to some non-opioid pharmacological effects of naloxone on the cardiac muscle is suggested.
authors.affiliation: Department of Biochemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Khananshvili
authors.forename: Y
authors.initials: Y
authors.lastname: Sarne
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007474:Ion Exchange; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009270:Naloxone / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D012508:Sarcolemma / Q000187:drug effects* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
chemical_list: D009294:Narcotics; D009270:Naloxone; D012964:Sodium; D002118:Calcium