title: Inhibition of the myocardial Ca(2+)-current (ICa) by the enantiomers of DPI 201-106 and BDF 8784.
abstract: 1. We studied the stereoselectivity of the effects of the enantiomers of the cardiotonic agent DPI 201-106 (4-[3'-(4"-benzhydryl-1"-piperazinyl)-2'-hydroxypropoxy]-1H-indole-2- carbonitrile, DPI) and its methyl-for-carbonitrile analogue BDF 8784 on cardiac calcium currents (ICa) of guinea-pig ventricular myocytes. The actions of the S- and R-enantiomers were compared with those of the racemate. 2. Racemic, S- and R-DPI depressed ICa in a concentration-dependent manner, the IC50 values were 1.1 mumol l-1 for racemic and S-DPI, and 1.2 mumol l-1 for R-DPI, respectively. Racemic, S- and R-BDF 8784 also reduced ICa, the respective IC50 values were 3.6 mumol l-1 for racemic BDF 8784, 1.3 mumol l-1 for S-BDF 8784 and 1.1 mumol l-1 for R-BDF 8784. 3. Neither the DPI nor the BDF 8784 enantiomers alter the time course of inactivation of ICa. The steady-state inactivation curve for ICa was shifted along the voltage axis to negative membrane potentials. The block of ICa was dependent on the membrane potential and increased with membrane depolarization. 4. Our findings indicate that DPI and BDF 8784 inhibit ICa in a non-stereoselective manner, which contrasts the opposite effects of the DPI enantiomers on Na+ channels.
authors.affiliation: Department of Pharmacology, University of Essen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Ravens
authors.forename: T
authors.initials: T
authors.lastname: Pfeifer
authors.forename: E
authors.initials: E
authors.lastname: Wettwer
authors.forename: M
authors.initials: M
authors.lastname: Grundke
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D015220:Calcium Channels; D002316:Cardiotonic Agents; D007211:Indoles; D010879:Piperazines; C060322:BDF 8784; C046261:DPI 201-106