Inhibition of sodium-calcium exchange in cardiac sarcolemmal membrane vesicles. 1. Mechanism of inhibition by amiloride analogues

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

OSTI ID:5173216

Slaughter, R S; Garcia, M L; Cragoe, Jr, E J; Reeves, J P; Kaczorowski, G J

The mechanism by which terminal guanidino nitrogen substituted analogues of amiloride inhibit Na-Ca exchange in purified cardiac sarcolemmal membrane vesicles has been investigated. These inhibitors block both Na/sub i/-dependent Ca/sup 2 +/ uptake and Na/sub 0/-dependent Ca/sup 2 +/ efflux. Inhibition of Na-Ca exchange monitored in K/sup +/ is noncompetitive vs /sup 45/Ca/sup 2 +/ but competitive vs /sup 22/Na/sup +/. Substitution of sucrose for K/sup +/ results in mixed kinetics of inhibition vs /sup 45/Ca/sup 2 +/, suggesting a complex interaction between inhibitor and carrier under this condition. Amiloride derivatives also block two other modes of carrier action: Na-Na exchange is inhibited in a competitive fashion with Na/sup +/ and kinetics of Ca-Ca exchange inhibition are mixed vs Ca/sup 2 +/ in either sucrose or K/sup +/. However, Ca-Ca exchange inhibition can be alleviated by increasing K/sup +/ concentration. Dixon analyses of Na-Ca exchange block with mixtures of inhibitors suggest that these agents are interacting at more than one site. In addition, Hill plots of inhibition are biphasic with Hill coefficients of 1 and 2 at low and high inhibitor concentration, respectively. These results indicate that amiloride derivatives are mechanisms-based inhibitors that interact at two classes of substrate-binding sites on the carrier; at low concentration they bind preferentially to a site that is exclusive for Na/sup +/, while at higher concentration they also interact at a site that is common for Na/sup +/, Ca/sup 2 +/, and K/sup +/

• Research Organization: Merck Institute for Therapeutic Research, Rahway, NJ (USA)
• OSTI ID: 5173216
• Journal Information: Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 27:7; ISSN BICHA
• Country of Publication: United States
• Language: English

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550601* -- Medicine-- Unsealed Radionuclides in Diagnostics
62 RADIOLOGY AND NUCLEAR MEDICINE
ALKALI METAL COMPOUNDS
ALKALI METAL ISOTOPES
ALKALINE EARTH ISOTOPES
ALKALINE EARTH METAL COMPOUNDS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BETA-PLUS DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BIOCHEMISTRY
BODY
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CALCIUM CHLORIDES
CALCIUM COMPOUNDS
CALCIUM HALIDES
CALCIUM ISOTOPES
CARDIOVASCULAR SYSTEM
CELL CONSTITUENTS
CELL MEMBRANES
CHEMISTRY
CHLORIDES
CHLORINE COMPOUNDS
DAYS LIVING RADIOISOTOPES
DIURETICS
DRUGS
EVEN-ODD NUCLEI
HALIDES
HALOGEN COMPOUNDS
HEART
INHIBITION
INTERMEDIATE MASS NUCLEI
ISOTOPES
KINETICS
LIGHT NUCLEI
MEMBRANE TRANSPORT
MEMBRANES
NUCLEI
ODD-ODD NUCLEI
ORGANS
RADIOISOTOPES
REACTION KINETICS
SODIUM 22
SODIUM CHLORIDES
SODIUM COMPOUNDS
SODIUM ISOTOPES
UPTAKE
YEARS LIVING RADIOISOTOPES