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)

Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

“…Garcia et al (12) reported that the inhibitory effect of bepridil on the Na + / Ca 2+ exchanger is direction-dependent, since Na o-dependent Ca 2+ efflux is more strongly inhibited than Nai-dependent Ca 2+ uptake in dog cardiac membrane vesicles. This is similar to the effect of dichlorobenzamil (17) but opposite to the effect of KB-R7943 which inhibits the Ca 2+ entry mode of Na + /Ca 2+ exchange more potently than the Ca 2+ efflux mode (17,29).…”

“…Garcia et al (12) using flux studies reported that bepridil inhibits Na + / Ca 2+ exchange in cardiac sarcolemmal membrane vesicles. However, electrophysiological studies on the effect of bepridil on Na + / Ca 2+ exchange current (INCX) have not been performed with cardiac myocytes.…”

Evidence for a Na+−Ca2+ exchanger in rat pancreatic ducts

“…However, since flufenamate did not decrease the Ca2+ transient induced by low Na+, Ca2+ did not enter via such channels, but rather in exchange for Na+. In our quest to provide evidence for the exchanger, we have also tried two putative blockers of the antiport -bepridil and S933240 [8,29]. However, our experience with these inhibitors is inconclusive.…”

“…In excitable tissues bepridil has been described as a blocker of the Naf-Ca2+ exchanger [8]. We tested this inhibitor at a concentration of lop6 mol/l in 10 experiments and at 10e5 mol/l in 4 experiments.…”

Up-Regulation of Bcl-2 through ERK Phosphorylation Is Associated with Human Macrophage Survival in an Estrogen Microenvironment

“…3A). To determine the route of Ca 2ϩ influx, we used voltage gated Ca 2ϩ channel blockers like pimozide for T-type channels (47) and verapamil for L-type channels (48) and Na ϩ /Ca 2ϩ exchange blockers like benzamil (49) and bepridil (50). Pimozide, bepridil or benzamil could not prevent Ca 2ϩ influx (data not shown), but verapamil was able to reduce both Ca 2ϩ peaks when added at two different time points, one before addition of E2 (Fig.…”