CHARACTERIZATION OF THE SENSITIVITY OF CARDIAC OUTWARDLY RECTIFYING K-III ANTIARRHYTHMICS - THE INFLUENCE OF INHIBITORY SULFONAMIDE DERIVATIVES( CHANNELS TO CLASS)
I. Benz et M. Kohlhardt, CHARACTERIZATION OF THE SENSITIVITY OF CARDIAC OUTWARDLY RECTIFYING K-III ANTIARRHYTHMICS - THE INFLUENCE OF INHIBITORY SULFONAMIDE DERIVATIVES( CHANNELS TO CLASS), Naunyn-Schmiedeberg's archives of pharmacology, 352(3), 1995, pp. 313-321
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.