We have synthesized and charted fluorescently labeled dihydropyridines (DHos) as probes for L-type Ca2+ channels. Racemic as well as (+)-and (-)-1,4-dihydro-2,6-dlmethryl4-(2-trifluoromethylphenyl)-3,5-pyrdlhncrboxylic acid 2-(aminoethyl)ethyl ester hydrochlorides were coupled to boron dipyrromethane (Bodipy) derivatives. (4,4-Diluoro-5,7-dlmethyl-4-bora-3a,4a-diaza)-3-(s-andaceuepropn add (DMBodipy)-DHP and (4,4-difluoro-7-styryl-4bora-3a Radloligand Biding. Rabbit skeletal muscle transversetubule or guinea pig-cortex membranes were prepared as described (30). Rabbit skeletal muscle L-type Ca2+ channels were partially purified by solubilization and chromatography on wheat germ agglutinin-Sepharose (31). Fluorescent DHPs and other drugs were diluted and added in dimethyl sulfoxide
In a randomized, double-blind, placebo-controlled, cross-over study 24 healthy volunteers were examined before and 2 h after oral administration of 80 mg (R,S)-, 40 mg (R)- and 40 mg (S)-propranolol.HCl; 8 of them received placebo in an additional run. During exercise on a bicycle ergometer and a rest period the rate pressure product was decreased by 80 mg (R,S)-propranolol.HCl (-32.8% p less than 0.0001) and 40 mg (S)-propranolol.HCl (-32.3%; p less than 0.0001), whereas 40 mg (R)-propranolol.HCl as well as placebo showed no effect. Corresponding binding inhibition experiments using (-)-(125I)iodocyanopindolol in a sarcolemma-enriched cardiac membrane preparation yielded a eudismic ratio of 179 for (S)- over (R)-propranolol. 2 h after oral application, stereospecific HPLC analysis revealed different individual concentrations in plasma of (R)- 22.3 +/- 21.7 ng/ml) and (S)-propranolol (30.4 +/- 26.9 ng/ml) when 80 mg of (R,S)-propranolol.HCl was administered. The plasma levels were similar when 40 mg of the pure enantiomer of (R)- (22.7 +/- 20.3 ng/ml) or (S)-propranolol.HCl (28.7 +/- 22.5 ng/ml) was applied. (R)- and (S)-propranolol are two substances with different pharmacodynamic and pharmacokinetic properties. As there are methods available to produce the optically pure enantiomers, they should be used rather than the racemic mixture.
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