Temperature-dependent modulation of (/sup 3/H)nitrendipine binding by the calcium channel antagonists verapamil and diltiazem in rat brain synaptosomes

Journal Article · Tue May 01 00:00:00 EDT 1984 · J. Pharmacol. Exp. Ther.; (United States)

OSTI ID:7017071

Boles, R G; Yamamura, H I; Schoemaker, H; Roeske, W R

Binding of the dihydropyridine calcium channel antagonist (/sup 3/H)nitrendipine to an intact rat brain mitochondrial-synaptosomal fraction (P/sub 2/) was specific, saturable, temperature-dependent and of high affinity (K/sub d/ . 115-467 pM). The effects of the calcium channel antagonists verapamil and diltiazem on (/sup 3/H)nitrendipine binding and their temperature dependence were investigated. At 0 and 25 degrees C, verapamil inhibited (/sup 3/H)nitrendipine binding incompletely in a manner consistent with an allosteric modulation and nearly independent of the incubation temperature. The effects of diltiazem, however, were found to be highly temperature-dependent. At 25 and 37 degrees C, 10 microM diltiazem enhanced (/sup 3/H)nitrendipine binding to values of 140 and 200% of control, respectively. At 0 degrees C, 10 microM diltiazem inhibited (/sup 3/H)nitrendipine binding to a value of 68% of control. Analysis of saturation isotherms at steady state demonstrated that at all temperatures studied the effects of verapamil and diltiazem on (/sup 3/H)nitrendipine binding were due to alterations in the ligand dissociation constant (K/sub d/). At 25 degrees C, these alterations were mediated by changes in the rate of ligand-receptor complex dissociation. Competition studies of verapamil and diltiazem at 25 and 0 degrees C indicate that the effects of these two drugs on (/sup 3/H)nitrendipine binding are mutually exclusive. We conclude that the binding of (/sup 3/H)nitrendipine is allosterically modulated by spacially related binding sites for verapamil and diltiazem.

• Research Organization: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson
• OSTI ID: 7017071
• Journal Information: J. Pharmacol. Exp. Ther.; (United States), Journal Name: J. Pharmacol. Exp. Ther.; (United States) Vol. 229:2; ISSN JPETA
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ALKALINE EARTH METALS
ANIMAL CELLS
BIOCHEMICAL REACTION KINETICS
CALCIUM
DOSE-RESPONSE RELATIONSHIPS
ELEMENTS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MEMBRANE TRANSPORT
METALS
NERVE CELLS
REACTION KINETICS
SOMATIC CELLS
TEMPERATURE DEPENDENCE
TRACER TECHNIQUES
TRITIUM COMPOUNDS