• Login
    View Item 
    •   JScholarship Home
    • Nobel Prize Winners
    • Peter Agre
    • View Item
    •   JScholarship Home
    • Nobel Prize Winners
    • Peter Agre
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Bepridil and cetiedil. Vasodilators which inhibit Ca2+-dependent calmodulin interactions with erythrocyte membranes

    Thumbnail
    View/Open
    jcinvest00135-0152.pdf (1.506Mb)
    Date
    1984-09
    Author
    Bennet, Vann
    Virshup, David
    Agre, Peter
    Metadata
    Show full item record
    Abstract
    Two new vascular smooth muscle relaxants, bepridil and cetiedil, were found to possess specific CaM-inhibitory properties which resembled those of trifluoperazine. Trifluoperazine, bepridil, and cetiedil inhibited Ca2+-dependent 125I-CaM binding to erythrocyte membranes and CaM activation of membrane Ca2+-ATPase with IC50 values of approximately 12, approximately 17, and approximately 40 microM, respectively. This does not appear to be the result of a nonspecific hydrophobic interaction since inhibition was not observed with micromolar concentrations of many other hydrophobic agents. The predominant inhibition of binding and Ca2+-ATPase activation was competitive with respect to CaM. Bepridil and cetiedil bind directly to CaM since these drugs displaced [3H]trifluoperazine from sites on CaM. Inhibition of Ca2+-ATPase and binding by the drugs was not due to interference with the catalytic activity of this enzyme since: (a) neither inhibition of CaM-independent basal Ca2+-ATPase activity nor inhibition of proteolytically-activated Ca2+-ATPase activities were produced by these agents, and (b) no drug-induced inhibition of CaM binding was detected when membranes were preincubated with these agents but washed prior to addition of 125I-CaM. Thus, bepridil and cetiedil competitively inhibit Ca2+-dependent interactions of CaM with erythrocyte membranes, most likely by a direct interaction between these drugs and CaM. The principal clinical actions of these drugs may be explained by their interactions with CaM or CaM-related proteins leading to reduced activation of Ca2+-regulated enzymes in certain other tissues, such as myosin light chain kinase in vascular smooth muscle.
    URI
    http://jhir.library.jhu.edu/handle/1774.2/33930
    Collections
    • Peter Agre

    Related items

    Showing items related by title, author, creator and subject.

    • VEGF immobilization and VEGFR2 trafficking and phosphorylation: in vitro and in vivo implications 

      Clegg, Lindsay Elizabeth Wendel; 0000-0001-8558-9341 (Johns Hopkins UniversityUSA, 2017-06-19)
      Modern drug development is marked by high failure rates in translation to the clinic. Further, many drugs that succeed in clinical trials work for only a fraction of patients. Systems pharmacology attempts to address these ...
    • Utility of Quantitative Analysis in Drug Development and Optimization of Anti-Infective Therapy 

      Hiruy, Hiwot (Johns Hopkins UniversityUSA, 2015-12-15)
      The cornerstone of anti-infective therapy is attainment of the effective target concentration of the drug at the site of infection; achieving this goal requires integration of the pharmacokinetic and pharmacodynamics ...
    • Mechanistic approaches for reactivation and elimination of latent HIV-1 

      Martin, Alyssa R. (Johns Hopkins UniversityUSA, 2017-02-09)
      Although HIV-1 can be adequately controlled by combination antiretroviral therapy (cART), it is still an incurable disease due in part to the latent reservoir that persists in resting CD4+ T cells (rCD4s). Latently infected ...

    DSpace software copyright © 2002-2016  DuraSpace
    Policies | Contact Us | Send Feedback
    Theme by 
    Atmire NV
     

     

    Browse

    All of JScholarshipCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    DSpace software copyright © 2002-2016  DuraSpace
    Policies | Contact Us | Send Feedback
    Theme by 
    Atmire NV