title: Inhibition of sodium-calcium exchange in cardiac sarcolemmal membrane vesicles. 2. Mechanism of inhibition by bepridil.
abstract: Bepridil, an antiarrhythmic agent, inhibits Na-Ca exchange in cardiac sarcolemmal membrane vesicles (Ki = 30 microM) by a novel mechanism, different from that determined for amiloride analogues [Slaughter, R. S., Garcia, M. L., Cragoe, E. J., Jr., Reeves, J. P., & Karczorowski, G. J. (1988) Biochemistry (preceding paper in this issue)]. Bepridil causes partial inhibition of Nai-dependent Ca2+ uptake but complete block of Nao-dependent Ca2+ efflux. Inhibition of Na-Ca exchange is noncompetitive vs Ca2+ but competitive vs Na+ in both K+ and sucrose. Bepridil also blocks Ca-Ca exchange, with or without K+ present. However, K+ has two effects on inhibition: it reduces the potency of bepridil and causes inhibition to become partial. Inhibition of Ca-Ca exchange displays noncompetitive kinetics vs Ca2+ in either sucrose or K+. Dixon analyses of Na-Ca exchange inhibition caused by mixtures of bepridil and amiloride analogues demonstrate that these compounds produce a competitive interaction at a common carrier site that is evident only at low concentrations of amiloride inhibitors. Hill plots of bepridil inhibition of Na-Ca and Ca-Ca exchange display unitary Hill coefficients. These results indicate that bepridil interacts at only one substrate-binding site, the site selective for Na+, where amiloride analogues also preferentially interact. However, unlike amiloride, bepridil does not interact at the common Na+, Ca2+-binding site of the carrier.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Biochemistry, Merck Institute for Therapeutic Research, Rahway, New Jersey 07065.
authors.forename: M L
authors.initials: ML
authors.lastname: Garcia
authors.forename: R S
authors.initials: RS
authors.lastname: Slaughter
authors.forename: V F
authors.initials: VF
authors.lastname: King
authors.forename: G J
authors.initials: GJ
authors.lastname: Kaczorowski
mesh_terms: D000818:Animals; D015764:Bepridil; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger; D013552:Swine
chemical_list: D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D011759:Pyrrolidines; D019831:Sodium-Calcium Exchanger; D015764:Bepridil; D012964:Sodium; D002118:Calcium