Differential effects of the new class III antiarrhythmic agents almokalant, E-4031 and D-sotalol, and of quinidine, on delayed rectifier currents in guinea pig ventricular myocytes.

OBJECTIVES: The effects of almokalant (4-[3-ethyl[3-(propylsulphinyl)propyl]-amino]-2-hydroxy-propoxy]- benzonitrile), E-4031 (1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulphonyl-amino- benzoyl)piperidine), d-sotalol, and quinidine were investigated on the delayed K+ rectifier current IK. The aim of the study was to compare the drug action on the two components of this current. METHODS: Membrane currents were measured in ventricular myocytes from guinea pig hearts with the whole cell voltage clamp technique. IK was activated during clamp steps from a holding potential of -40 mV to test potentials -30 and +50 mV. The tail current Itail was measured upon stepping back to holding potential. RESULTS: In control experiments. IK and Itail declined spontaneously ("run down"). With 300 ms long test pulses to +50 mV, only d-sotalol (10(-4) M) caused a significant further decrease in IK, whereas all four agents significantly reduced Itail (almokalant 10(-6) M, E-4031 10(-7) M, quinidine 10(-5) M). When tested with 1 s long clamp steps at various potentials almokalant (3 x 10(-6) M), E-4031 (10(-6) M), quinidine (10(-5) M), and d-sotalol (10(-4) M) reduced IK in the potential range between -20 and +40 mV, yielding a bell shaped inward rectifying drug sensitive current. Itail was reduced by almokalant and E-4031 over the whole voltage range with saturation of block positive to +20 mV. Similar reductions with quinidine but not with d-sotalol were also significant. With rest pulses to +50 mV of increasing duration (25 ms-4000 ms), Itail developed with a faster time course than IK and therefore the ratio of Itail/IK declined with pulse duration. With almokalant and E-4031, this ratio became independent of test pulse duration. For 250 ms pulses, Itail/IK was also significantly reduced by d-sotalol and quinidine. CONCLUSION: Inhibition of the rapidly activating inwardly rectifying component of IK is prominent with almokalant and E-4031 and less pronounced with d-sotalol and quinidine. Since inhibition of this component prolongs the cardiac action potential, it should contribute to the antiarrhythmic properties of the agents.

Characterization of Ca(2+)-antagonistic effects of three metabolites of the new antihypertensive agent naftopidil, (naphthyl)hydroxy-naftopidil, (phenyl)hydroxy-naftopidil, and O-desmethyl-naftopidil.

The newly developed antihypertensive agent naftopidil blocks alpha 1-adrenoceptors and inhibits Ca2+ entry via potential-dependent channels in vascular and cardiac muscle. It is extensively metabolized in vivo. Since it is of interest whether its metabolites are still pharmacologically active, we have characterized the effects of (naphthyl)hydroxy-naftopidil (NHN), (phenyl)hydroxy-naftopidil (PHN), and O-desmethyl-naftopidil (DMN) in various isolated preparations of the guinea pig heart. In constant-flow Langendorff hearts, the compounds decreased force of contraction by 66-81% and slowed spontaneous heart rate by 28-48%. DMN reduced perfusion pressure by 33%. The fibrillation threshold, which was measured as the strength of alternating current required to induce ventricular fibrillation, increased more than 10-fold. In papillary muscles, 3 x 10(-5) M of all compounds reduced force of contraction (pD2 values approximately 5.5) and shortened the action potential duration in the plateau phase. The maximum depolarization velocity (dV/dtmax) was slightly reduced (10-21%) by NHN, PHN, and DMN. In voltage-clamped ventricular cardiomyocytes, the calcium current ICa was depressed by the three compounds (10(-6)-10(-4) M) in a concentration-dependent manner. In conclusion, the three naftopidil metabolites investigated have pharmacological activities similar to those of their parent compound and hence could contribute to the in vivo effects of naftopidil.

Inhibition of the myocardial Ca(2+)-current (ICa) by the enantiomers of DPI 201-106 and BDF 8784.

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.