Characterization of the sensitivity of cardiac outwardly-rectifying K+ channels to class III antiarrhythmics: the influence of inhibitory sulfonamide derivatives.

Elementary K+ currents through cardiac 66 pS outwardly-rectifying K+ channels isolated from cultured neonatal rat cardiocytes were recorded in the inside-out patch configuration. By analyzing the influence of inhibitory sulfonamide derivatives, the block phenomenology evoked by these 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, within 3 min or longer, a several-fold enhanced steady state level. Nevertheless, the novel sulfonamide derivative HE93 (10-100 mumol/l) depressed NPo significantly within some hundred milliseconds on cytosolic administration with a calculated IC50 value of 38 mumol/l. Drug-induced channel blockade mainly emerged from an increased life time of the prolonged C2-state; tau closed (2) rose (at 100 mumol/l) to 269 +/- 20%. A C1-C2 reaction scheme can adequately describe closed time kinetics in the presence of HE93 but the occurrence of a specific, drug-evoked ultralong (< or = 60 ms) C-state and mainly underlying the NPo depression cannot be excluded. Sotalol (100 mumol/l) caused the same block phenomenology although a 2.6-fold larger IC50 value (half maximal inhibitory concentration) suggests a smaller potency to depress channel activity. Despite a close structural relationship with the both compounds HE93 and sotalol, glibenclamide (100 mumol/l) exerted no significant inhibitory influence (IC50 = 530 mumol/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) mol-1 s-1 to shorten their 0-state, as a sign of open channel blockade.(ABSTRACT TRUNCATED AT 250 WORDS)