title: Effects of the calcium antagonists perhexiline and cinnarizine on vascular and cardiac contractile protein function.
abstract: The weakly basic, lipophilic Ca++ antagonists perhexiline and cinnarizine have been compared with the calmodulin inhibitor W-7 and the cardiotonics Vardax and APP-201-533 for the ability to modulate Ca++-dependent contractile protein interactions directly, as well as Ca++-calmodulin-mediated myosin light chain phosphorylation, in arterial actomyosin or cardiac myofibrils. Both perhexiline and cinnarizine inhibited arterial myosin P-light chain phosphorylation and superprecipitation of arterial actomyosin over the concentration range of 10 to 200 microM. Concomitant inhibition of arterial superprecipitation and phosphorylation by perhexiline (IC50 = 33 microM) and cinnarizine (IC50 = 60 microM) was similar to W-7 (IC50 = 35 microM), and was characterized by a rightward shift in the pCa superprecipitation and pCa-light chain phosphorylation relationships, depressed maximum activity and attenuation by 2 microM exogenous calmodulin. However, whereas inhibition of superprecipitation and P-light chain phosphorylation by W-7 was equal at different Mg++ concentrations, relatively greater inhibition with perhexiline and less inhibition with cinnarizine was apparent as the free Mg++ concentration was lowered. In cardiac myofibrils prepared from both bovine and canine ventricles, perhexiline stimulated Mg-adenosine triphosphatase (ATPase) activity and cinnarizine was without effect, whereas W-7 significantly depressed ATPase activity. Perhexiline was 10-fold more potent and 3-fold more efficacious than either Vardax or APP-201-533 in canine cardiac myofibrils. Whereas APP-201-533 increased Ca++ sensitivity and maximum ATPase activity (Vmax), perhexiline increased Ca++ sensitivity, but not Vmax, and W-7 depressed both parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.forename: P J
authors.initials: PJ
authors.lastname: Silver
authors.forename: J
authors.initials: J
authors.lastname: Dachiw
authors.forename: J M
authors.initials: JM
authors.lastname: Ambrose
authors.forename: P B
authors.initials: PB
authors.lastname: Pinto
mesh_terms: D000251:Adenosine Triphosphatases / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002417:Cattle; D002936:Cinnarizine / Q000494:pharmacology*; D003285:Contractile Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism; D010480:Perhexiline / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D003285:Contractile Proteins; D007093:Imidazoles; D010879:Piperazines; D013449:Sulfonamides; D002936:Cinnarizine; C017967:W 7; D000251:Adenosine Triphosphatases; D009218:Myosins; C029758:sulmazole; D008274:Magnesium; D010480:Perhexiline; D002118:Calcium