Inhibition of sodium-calcium exchange in cardiac sarcolemmal membrane vesicles. 2. Mechanism of inhibition by bepridil

Journal Article · Tue Apr 05 04:00:00 EDT 1988 · Biochemistry; (United States)

DOI:https://doi.org/10.1021/bi00407a024· OSTI ID:5210612

Garcia, M L; Slaughter, R S; King, V F; Kaczorowski, G J

Bepridil, an antiarrhythmic agent, inhibits Na-Ca exchange in cardiac sarcolemmal membrane vesicles by a novel mechanism, different from that determined for amiloride analogues. Bepridil causes partial inhibition of Na/sub o/-dependent /sup 45/Ca/sup 2 +/ efflux. Inhibition of Na-Ca exchange is noncompetitive vs Ca/sup 2 +/ but competitive vs Na/sup +/ in both K/sup +/ and sucrose. Bepridil also blocks Ca-Ca exchange, with or without K/sup +/ present. However, K/sup +/ 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 Ca/sup 2 +/ in either sucrose of K/sup +/. 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 a 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/sup +/, where amiloride analogues also preferentially interact. However, unlike amiloride, bepridil does not interact at the common Na/sup +/, Ca/sup 2 +/-binding site of the carrier. During stimulation of Ca-Ca exchange, K/sup +/ may bind at other sites besides the site selective for Na/sup +/, because in addition to being competitive with bepridil, it prevents complete abolition of Ca-Ca exchange, suggesting that this Na/sup +/ site is not involved in carrier turnover. These findings indicate the bepridil is a mechanisms-based Na-Ca exchange inhibitor that interacts at a transporter site which binds Na/sup +/ but not Ca/sup 2 +/

• Research Organization: Merck Institute for Therapeutic Research, Rahway, NJ (USA)
• OSTI ID: 5210612
• Journal Information: Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 27:7; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ALKALI METAL COMPOUNDS
ALKALINE EARTH ISOTOPES
ALKALINE EARTH METAL COMPOUNDS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BIOCHEMISTRY
BODY
CALCIUM 45
CALCIUM CHLORIDES
CALCIUM COMPOUNDS
CALCIUM HALIDES
CALCIUM ISOTOPES
CARDIOVASCULAR AGENTS
CARDIOVASCULAR SYSTEM
CELL CONSTITUENTS
CELL MEMBRANES
CHEMISTRY
CHLORIDES
CHLORINE COMPOUNDS
DAYS LIVING RADIOISOTOPES
DOSE-RESPONSE RELATIONSHIPS
DRUGS
EVEN-ODD NUCLEI
HALIDES
HALOGEN COMPOUNDS
HEART
INHIBITION
INTERMEDIATE MASS NUCLEI
ISOTOPES
KINETICS
MEMBRANE TRANSPORT
MEMBRANES
NUCLEI
ORGANS
RADIOISOTOPES
REACTION KINETICS
SODIUM CHLORIDES
SODIUM COMPOUNDS
UPTAKE