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

Abstract

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.-react.)} 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 μmol/l) depressed NP _o significantly within some hundred milliseconds on cytosolic administration with a calculated IC₅₀ value of 38 μmol/1. Drug-induced channel blockade mainly emerged from an increased life time of the prolonged C₂-state; τ_{closed (2)} rose (at 100 μmol/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-evolved ultralong ($\bar >$ 60 ms) C-state and mainly underlying the NP _o depression cannot be excluded. Sotalol (100 μmo1/1) 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 μmol/l) exerted no significant inhibitory influence (IC₅₀ = 530 μmo1/1 on K⁺ channel activity. Instead, this sulfonylurea interfered with open K⁺ channels with an association rate constant of 8.2 ± 3.8 × 10⁶ mol⁻¹ s⁻¹ to shorten their 0-state, as a sign of open channel blockade. Thus, cardiac K⁺ _outw.-rect.) channels discriminate among these drugs which provides functional evidence in support of the idea that they accomodate multiple drug receptors, one of them involved in depressing channel activity and the other receptor involved in influencing open state kinetics.