CHARACTERIZATION OF THE SENSITIVITY OF CARDIAC OUTWARDLY RECTIFYING K-III ANTIARRHYTHMICS - THE INFLUENCE OF INHIBITORY SULFONAMIDE DERIVATIVES( CHANNELS TO CLASS)

Elementary K+ currents through cardiac 66 pS outwardly-rectifying K+ c hannels isolated from cultured neonatal rat cardiocytes were recorded in the inside-out patch configuration. By analyzing the influence of i nhibitory sulfonamide derivatives, the block phenomenology evoked by t hese class III antiarrhythmic drugs was studied. After isolation from their cellular environment, K-(outw.-rect.(+)) channels became usually upregulated so that open probability increased with time to reach, wi thin 3 min or longer, a several-fold enhanced steady state level. Neve rtheless, the novel sulfonamide derivative HE93 (10-100 mu mol/l) depr essed NPo significantly within some hundred milliseconds on cytosolic administration with a calculated IC50 value of 38 mu mol/l. Drug-induc ed channel blockade mainly emerged from an increased life time of the prolonged C-2-state; tau(closed(2)) rose (at 100 mu mol/l) to 269 +/- 20%, A C-1-C-2 reaction scheme can adequately describe closed time kin etics in the presence of HE93 but the occurrence of a specific, drug-e voked ultralong (equal to or greater than 60 ms) C-state and mainly un derlying the NPo depression cannot be excluded. Sotalol (100 mu mol/l) caused the same block phenomenology although a 2.6-fold larger IC50 v alue (half maximal inhibitory concentration) suggests a smaller potenc y to depress channel activity. Despite a close structural relationship with the both compounds HE93 and sotalol, glibenclamide (100 mu mol/l ) exerted no significant inhibitory influence (IC50 = 530 mu mol/l) on K+ channel activity. Instead, this sulfonylurea interfered with open K+ channels with an association rate constant of 8.2 +/- 3.8 x 10(6) m ol(-1) s(-1) to shorten their O-state, as a sign of open channel block ade. Thus, cardiac K-(outw.-rect.(+)) channels discriminate among thes e drugs which provides functional evidence in support of the idea that they accomodate multiple drug receptors, one of them involved in depr essing channel activity and the other receptor involved in influencing open state kinetics.