title: Berbamine increases myocardial contractility via a Ca2+-independent mechanism.
abstract: Berbamine (BM), a natural compound derived from Berberis vulgaris L, has been reported to inhibit cardiac contractile function at higher concentrations. Here, we report that BM had concentration-dependent biphasic effects on myocardial contraction in Langendorff-perfused rat hearts, that is, at lower concentrations (30-100 nM), it displayed positive inotropic and lusitropic effects, whereas at a higher concentration of 1 μM, it caused a negative inotropic effect after an initially weak increase. These effects were further confirmed in cardiomyocytes isolated from the left ventricles of rats. Moreover, the increased cell shortening by BM at concentrations from 0.1 to 100 nM was not associated with an alteration of intracellular Ca transients. Consistently, at 30 nM, BM shifted the cell shortening--Ca transient relationship curve induced by cumulative elevation of extracellular Ca concentration to the left. Furthermore, BM significantly increased membrane-bound but not filament-bound protein kinase C epsilon (PKCε) in the isolated hearts and cardiomyocytes. Such a translocation was inhibited by PKCε-specific inhibitor PKCε V1-2 concomitant with the abolishment of the BM-induced increase in contraction. These findings reveal the positive inotropic effect of BM in the myocardium and demonstrate that BM increases myocardial contractility by increasing myofilament Ca sensitivity via a PKCε-dependent signaling pathway.
authors.affiliation: From the Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institute for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
authors.forename: Cai-Mei
authors.initials: CM
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Zheng
authors.forename: Huang-Tian
authors.initials: HT
authors.lastname: Yang
mesh_terms: D000818:Animals; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D044182:Benzylisoquinolines; D002118:Calcium; C027870:berbamine