Interaction of the calcium antagonist fantofarone with phospholipids: electrostatic effects.

The binding of fantofarone, a novel calcium channel antagonist, to cytoplasmic membranes and lipid vesicles has been studied by means of its fluorescence. The binding characteristics (dissociation constant Kd and total number of binding sites Bmax) were determined using saturation isotherms. In brain synaptic and cardiac sarcolemmal membranes, fantofarone binds to a single site with a Kd value of approximately 1.

Binding of fantofarone, a novel Ca2+ antagonist, to serum albumin: a fluorescence study.

Using the fluorescent properties of fantofarone, we have studied the interactions between this novel calcium entry blocker and human and bovine serum albumins. Binding of fantofarone, which is poorly fluorescent in aqueous buffer, resulted in a large increase in the fluorescent signal (lambda ex = 335 nm, lambda em = 395 nm). Fantofarone bound to a single site with a dissociation constant (Kd) of 11-12 x 10(-6) M.

31P nuclear magnetic resonance study of the effects of the calcium ion channel antagonist fantofarone on the rat heart.

The biochemical and mechanical effects of a new calcium ion channel antagonist, fantofarone ((2-isopropyl-1-((4-(3-(N-methyl-N-(3,4-dimethoxy-beta-phenethyl)-amino) propyloxy)benzenesulfonyl))-indolizine), on isovolumic perfused rat heart have been assessed by using 31P nuclear magnetic resonance (NMR) spectroscopy together with simultaneous monitoring of myocardial mechanical function. Cytosolic pH and phosphocreatine, adenosine triphosphate and inorganic phosphate contents were monitored by using 31P NMR. Heart rate, coronary flow and left ventricular developed pressure were measured routinely to assess mechanical function.

Fluorescent studies on the interaction between a novel Ca2+ antagonist, SR 33557, and membrane lipids.

The fluorescent properties of SR 33557, a novel calcium entry blocker, have been characterized in solution and when interacting with phospholipid vesicles and natural membranes. The intensity and lifetime of fluorescence emission increased directly as a function of the decrease in the solvent dielectric constant (epsilon) with no change in the emission wavelength maxima. The quantum yield and the fluorescence lifetime in dioxane were 0.

SR 33557, a novel calcium entry blocker. II. Interactions with 1,4-dihydropyridine, phenylalkylamine and benzothiazepine binding sites in rat heart sarcolemmal membranes.

We have assessed the binding characteristics of a structurally novel calcium entry blocker, SR 33557, to purified rat heart sarcolemma. SR 33557 prevented completely the binding of (+)-[3H]PN200-110, (-)-[3H]D888 and cis-(+)-[3H]diltiazem to their specific binding sites in an apparently competitive manner (nH congruent to 1.0) and with a high affinity (Ki = 0.

Differential effects of amiodarone and propranolol on lipid dynamics and enzymatic activities in cardiac sarcolemmal membranes.

The amphiphilic cationic cardioactive drugs (pindolol, propranolol and amiodarone) were tested for their effects on lipid dynamics (measured by fluorescence depolarization) and on enzymatic activities up to 1 mM in purified cardiac sarcolemmal vesicles from adult rat. The vesicles were enriched 12- to 37-fold (with respect to tissue homogenate) in Na+/K+ ATPase, K+-stimulated p-nitrophenylphosphatase, 5'nucleotidase and adenylate cyclase, all of which are believed to be components of sarcolemma. Phospholipids and cholesterol content were enriched 5- and 13-fold respectively.

Amiodarone induced modifications of the phospholipid physical state. A fluorescence polarization study.

The effects of an antiarrhythmic and antianginal drug, amiodarone, on the physical state of membrane phospholipids was investigated by means of fluorescence polarization using the apolar probe 1,6 diphenyl-1,3,5-hexatriene incorporated in the hydrocarbon core. Multilamellar vesicles were prepared from neutral phospholipids (egg phosphatidylcholine, synthetic saturated phosphatidylcholine) alone or mixed with cholesterol or various lipids representative of the main lipid classes. Amiodarone reduces the temperature of the gel to liquid-crystalline phase transition and either increases or decreases lipid mobility in the gel or liquid-crystalline phase.

Amiodarone partitioning with phospholipid bilayers and erythrocyte membranes.

The apparent partition coefficient (P) of amiodarone between aqueous buffer and lipid vesicles or erythrocyte ghosts was determined by equilibrium distribution using [125I]amiodarone as a tracer. The lipid vesicles consisted of total lipids extracted from erythrocyte or of egg phosphatidylcholine alone or mixed with a varying amount of stearic acid, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, or cholesterol. All the conditions yielded a similar value of P (P approximately equal to 17,000).

Effect of amiodarone on membrane fluidity and Na+/K+ ATPase activity in rat-brain synaptic membranes.

In rat-brain synaptic membranes at a fixed temperature (37 degrees C), amiodarone dose-dependently inhibits the Na+/K+ ATPase activity (IC50 approximately equal to 2.10(-5)M) and produces a linear increase in the degree of fluorescence depolarization (P) of 1,6-diphenylhexatriene embedded in the lipid matrix. Amiodarone has no effect on Mg++ ATPase and K+PNPase activity up to 3.