Publications [#112830] of G Vann V. Bennett

Papers Published

1. P Agre, D Virshup, V Bennett, Bepridil and cetiedil. Vasodilators which inhibit Ca2+-dependent calmodulin interactions with erythrocyte membranes., The Journal of clinical investigation, UNITED STATES, vol. 74 no. 3 (September, 1984), pp. 812-20, ISSN 0021-9738
   (last updated on 2003/02/18)

   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.

   Keywords:
   Adult • Azepines • Bepridil • Calcium • Calcium Channel Blockers • Calcium-Transporting ATPases • Calmodulin • Calmodulin-Binding Proteins • Erythrocyte Membrane • Humans • Kinetics • Phosphoprotein Phosphatase • Pyrrolidines • Trifluoperazine • Vasodilator Agents • blood • blood* • drug effects • metabolism* • pharmacology • pharmacology*