KCB-328 - A NOVEL CLASS-III ANTIARRHYTHMIC AGENT WITH LITTLE REVERSE FREQUENCY-DEPENDENCE IN ISOLATED GUINEA-PIG MYOCARDIUM

The effects of 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4- dime thoxyphenethyl)-N-methylamino] ethane hydrochloride (KCB-328), in comp arison with those of dofetilide, were studied on the action potentials (APs) of isolated guinea pig papillary muscles. KCB-328 (0.003-3 mu M ) concentration-dependently prolonged the AP duration at 90% repolariz ation (APD(90)) at 1- and 3-Hz pacing, and the concentration-response relations at 1 and 3 Hz resemble each other. Dofetilide (0.001-1 mu M) also produced the concentration-dependent prolongation of APD(90) but more pronouncedly at 1 than at 3 Hz, demonstrating the reverse freque ncy-dependent effect. KCB-328 at 0.03, 0.1, 0.3, and 1 mu M increased APD(90) by 11 +/- 1, 19 +/- 1, 25 +/- 1, and 29 +/- 1% at 3 Hz and by 9 +/- 1, 19 +/- 2, 27 +/- 2, and 33 +/- 2% at 1 Hz, respectively. Prol ongation of the effective refractory period (ERP) by each drug is para llel to those of APD(90) at each pacing frequency. KCB-328 modified ne ither the maximal velocity of depolarization, amplitude of AP, and res ting membrane potential in the fast APs, nor any parameters of the slo w APs. In a separate experiment, the effects of KCB-328 on the ERP of contractile response (ERPc) of excised guinea-pig papillary muscles al so were studied at 1 and 3 Hz. KCB-328 (0.01-10 mu M) lengthened the E RPc in a concentration-dependent and frequency-independent manner as i n the electrophysiologic results. This frequency-independent ERPc prol ongation by KCB-328 was not influenced by increased extracellular K+ c oncentration from 4 to 10 mM. These results suggest that KCB-328 might be a selective class III agent with effects that are relatively frequ ency independent.