Bepridil and cetiedil. Vasodilators which inhibit Ca2+-dependent calmodulin interactions with erythrocyte membranes.
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.
D000328:Adult; D001381:Azepines / Q000494:pharmacology*; D015764:Bepridil; D002118:Calcium / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000097:blood; D002147:Calmodulin / Q000097:blood*; D002148:Calmodulin-Binding Proteins; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010749:Phosphoprotein Phosphatases / Q000097:blood*; D011759:Pyrrolidines / Q000494:pharmacology*; D014268:Trifluoperazine / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D001381:Azepines; D002121:Calcium Channel Blockers; D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D011759:Pyrrolidines; D014665:Vasodilator Agents; D014268:Trifluoperazine; C006955:cetiedil; D015764:Bepridil; D010749:Phosphoprotein Phosphatases; D000252:Calcium-Transporting ATPases; D002118:Calcium