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  • Title: Effects of the two enantiomers, S-16257-2 and S-16260-2, of a new bradycardic agent on guinea-pig isolated cardiac preparations.
    Author: Pérez O, Gay P, Franqueza L, Carrón R, Valenzuela C, Delpón E, Tamargo J.
    Journal: Br J Pharmacol; 1995 Jul; 115(5):787-94. PubMed ID: 8548178.
    Abstract:
    1. The electromechanical effects of two enantiomers, S-16257-2 (S57) and S-16260-2 (R60), were studied and compared in guinea-pig isolated atria and ventricular papillary muscles. The possible stereoselectivity of the interaction on the cardiac Na+ channel was analysed by comparing the effects of the two enantiomers on the onset and recovery kinetics of the frequency-dependent Vmax block. 2. In spontaneously beating right atria, S57 and R60 (10(-8)M-10(-4M) exerted a negative chronotropic effect (pIC50 = 5.07 +/- 0.19 and 4.76 +/- 0.18, respectively) and prolonged the sinus node recovery time, this effect being more marked with S57. In electrically driven left atria, S57 decreased (P < 0.05) contractile force only at 10(-4M) and R60 at concentrations > or = 5 x 10(-5M), whereas in papillary muscles the negative inotropic effect appeared at concentrations > 10(-5M). 3. In papillary muscles driven at 1 Hz, S57 and R60 at concentrations higher than 5 x 10(-6M) produced a concentration-dependent decrease in the maximum upstroke velocity (Vmax) and amplitude of the cardiac action potential without altering the resting membrane potential or the action potential duration. S57 and R60 had no effect on the characteristics of the slow action potentials elicited by isoprenaline in ventricular muscle fibres depolarized in high K+ (27 mM) solution. 4. At 5 x 10(-5M), S57 and R60 produced a small tonic Vmax block. However, in muscles driven at rates between 0.5 and 3 Hz both enantiomers produced an exponential decline in Vmax (frequency-dependent Vmax block) which augmented at higher rates of stimulation. The onset and offset rates of the frequency-dependent Vmax block were similar for both drugs. Both S57 and R60 prolonged the recovery time constant from the frequency-dependent block from 20.1 +/- 2.9 ms to 2-3 s.5. At 5 x 10-5 M, S57 and R60 shifted the membrane responsiveness curve in a hyperpolarizing direction.6. It can be concluded that S57 and R60, the two enantiomers of the new bradycardic agent, produced a similar frequency-dependent Vmax block which indicated that the interaction with the Na+ channel was not stereospecific. The analysis of the onset and offset kinetics of the frequency-dependent Vmax block suggested that both enantiomers can be considered as Na+ channel blockers with intermediate kinetics,e.g., class IA antiarrhythmic drugs.
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