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R Laruel

Publications and source records attributed to R Laruel.

9 recordsLinked to original sources
PubMed1992

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 0.90 and 11.1 nsec, respectively. In various vesicles and in erythrocyte ghosts, SR 33557 was shown to be located in a lipidic environment corresponding to an epsilon of 30 congruent to 40. At 25 degrees, the dissociation constant (Kd) was 1.1-7.3 x 10(-6) M with a maximum of 15 SR 33557 molecules bound per 100 phospholipid molecules. When interacting with phospholipids, SR 33557 exhibited two fluorescence lifetimes (approximately 13 and 4 nsec) with the fractional contribution of 81 and 19% of the total decay, respectively. Binding of SR 33557 was enthalpy-driven. Both intensity of fluorescence emission and of fluorescence polarization of SR 33557 were indices of phase transitions in phospholipid vesicles. Thus, SR 33557 has fluorescent properties which may be of use in the study of its mode of action in biological media.

Animals↗
PubMed1990

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 = 0.5-2.0 nM). Equilibrium and kinetic studies suggest that SR 33557 does not act as a simple competitive antagonist at the 1,4-dihydropyridine, the phenylalkylamine or the benzothiazepine-selective sites associated with the L-type calcium channel: 1) inhibition of (-)-[3H]D888 and cis-(+)-[3H]diltiazem binding by SR 33557 resulted in a decrease in maximum binding, 2) cis-(+)-diltiazem and (+)-PN200-110 allosterically increased the inhibition of (+)-[3H]PN200-110 binding and of (-)-[3H]D888 and cis-(+)-[3H]diltiazem binding by SR 33557, respectively and 3) dissociation kinetics of the three radioligands were accelerated by SR 33557. Calcium (in millimolar concentrations) decreased the apparent affinity of SR 33557 for its high-affinity binding sites. This observation was similar to that seen with the phenylalkylamines and cis-(+)-diltiazem, but contrasted from that seen with the 1,4-dihydropyridines. These results indicate that SR 33557 interacts with a high affinity to a novel binding site associated with the L-type calcium channel and has a strong negative allosteric interaction with the well-characterized binding sites for 1,4-dihydropyridines, phenylalkylamines and benzothiazepines.

Animals↗
PubMed1989

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. There was very little contamination of the sarcolemmal vesicles by sarcoplasmic reticulum (as judged by Ca2+ ATPase and glucose-6-phosphatase activities) or mitochondria (as judged by cytochrome-c-oxidase activity). Pindolol had no effect on lipid dynamics and enzyme activities except for the isoproterenol-stimulated adenylate cyclase. The latter was also totally inhibited at 1 microM by propranolol which inhibited Mg2+ ATPase and increased fluidity above 20 microM. Amiodarone affected all the enzyme activities (except Na+/K+ ATPase): isoproterenol-stimulated adenylate (IC50 = 30 microM), Mg2+ ATPase (IC50 = 20 microM) and K+-stimulated-p-nitrophenylphosphatase were inhibited; 5'nucleotidase was activated above 2 microM. By contrast with propranolol, amiodarone decreased lipid mobility. The effect was linear with the concentration of the drug above 1 microM.

4-Nitrophenylphosphatase↗
PubMed1986

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. In the gel state, the lipid mobility depends on drug concentration, degree of ionization and the length of the lipid acyl chains. In the liquid-crystalline state, the decreased lipid mobility which is concentration-dependent is essentially due to hydrophobic interactions. Amiodarone increases the lipid order parameter to the same extent as cholesterol. The data suggested that amiodarone is a rigid molecule deeply buried in the hydrocarbon core of the lipid and that amiodarone-lipid interactions are mainly hydrophobic.

Amiodarone↗
PubMed1985

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 3.10(-4)M. Studies carried out at different temperatures indicate that 10(-5)M amiodarone inhibits the Na+/K+ ATPase and decreases the lipid fluidity at all the temperatures studied (9 - 40 degrees C). The compound significantly displaces the temperature of transition observed around 20 degrees C in both Na+/K+ ATPase activity and lipid fluidity to 24 degrees C with no changes in slopes. The results suggest that part of the selective inhibition of Na+/K+ ATPase activity by amiodarone could be due to the effects of the drug on lipid dynamics.

Amiodarone↗
PubMed1985

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). The log value of the partition coefficient of the neutral form of the drug is log PN = 5.95. The value of the extrapolated 1-octanol-buffer partition coefficient is log PN,oct = 6.66. Partition coefficient measurements on erythrocyte ghosts suggested that amiodarone partitioned to a similar extent in the protein and lipid content of the membrane.

Amiodarone↗