Characterization of the slow calcium channel binding sites for [3H]SR 33557 in rat heart sarcolemmal membranes.
SR 33557 represents a new class of compounds (indolizine sulfone) that inhibit L-type Ca2+ channels. [3H]SR 33557 has been shown to bind with high affinity (Kd congruent to 0.36 nM, calculated from saturation isotherms and association/dissociation kinetics) to a single class of sites in a purified preparation of rat cardiac sarcolemmal membranes. The binding was found to be saturable and reversible. The maximal binding capacity was in approximately 1:1 stoichiometry with that of other Ca2+ channel antagonists. Various divalent cations (Mg2+, Mn2+, Ca2+, Ba2+, and Cd2+) were shown to inhibit specific [3H]SR 33557 binding, with Cd2+ being the most potent. Among several receptor or channel ligands (including omega-conotoxin and Na+ and K+ channel modulators), only the L-type Ca2+ channel antagonists were found to displace [3H]SR 33557. However, dihydropyridines, phenylalkylamines, benzothiazepines, and diphenylbutylpiperidines were found to inhibit [3H]SR 33557 in a noncompetitive manner as demonstrated by displacement and saturation experiments in addition to dissociation kinetics. From these results, we suggest that SR 33557 binds with high affinity to a unique site on the L-type Ca2+ channel found in rat cardiac sarcolemmal membranes.
Chatelain
P
P
Sanofi-Labaz Research Centre, Brussels, Belgium.
Beaufort
P
P
Meysmans
L
L
Clinet
M
M
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D015220:Calcium Channels / Q000378:metabolism*; D002412:Cations; D004095:Dihydropyridines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007212:Indolizines / Q000494:pharmacology*; D007700:Kinetics; D010627:Phenethylamines / Q000494:pharmacology*; D051381:Rats; D012508:Sarcolemma / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium
D015220:Calcium Channels; D002412:Cations; D004095:Dihydropyridines; D007212:Indolizines; D010627:Phenethylamines; D014316:Tritium; C059901:fantofarone