P. Daleau et J. Turgeon, TRIAMTERENE INHIBITS THE DELAYED RECTIFIER POTASSIUM CURRENT (I-K) INGUINEA-PIG VENTRICULAR MYOCYTES, Circulation research, 74(6), 1994, pp. 1114-1120
In humans, proarrhythmia during therapy with action potential-prolongi
ng drugs can be associated with hypokalemia often provoked by concomit
ant administration of diuretic agents. Consequently, therapy with clas
s III antiarrhythmics and K+-sparing diuretics, such as triamterene, m
ay be indicated. Triamterene, along with its K+-sparing properties, ex
hibits other pharmacological effects. In the heart, it can increase ac
tion potential duration (guinea pig atria and papillary muscles), prot
ect against reperfusion-induced arrhythmias (rat), and increase the QT
interval (humans). Therefore, studies were undertaken to assess effec
ts of triamterene on cardiac K+ repolarizing currents. Guinea pig Vent
ricular myocytes were superfused at 30 degrees C with Cd2+-containing
solution to block I-si and held at -40 mV to inactivate I-Na. Currents
were measured in the whole-cell configuration of the patch-clamp tech
nique. The delayed rectifier outward current (I-K) was elicited by sho
rt (250-millisecond) and long (5000-millisecond) depolarizing pulses,
and time-independent currents were assessed by a rapid ramp test proto
col. After high-voltage long pulses (+50 mV; 5000 milliseconds), tail
current amplitude of the slow component of I-K (I-Ks) was decreased 36
+/-6% (n=6) and 51+/-8% (n=6) by triamterene 10(-5) and 10(-4) mol/L,
respectively. After low-voltage short pulses (-20 mV; 250 milliseconds
), tail current amplitude corresponding essentially to the rapid compo
nent of I-K (I-Kr) was decreased only 14+/-11% (n=9) and 19+/-10% (n=1
0) by triamterene 10(-5) and 10(-4) mol/L, respectively. These results
were confirmed under conditions of pure I-Ks (block of I-si by E-4031
) and pure I-Kr (block of I-si with nisoldipine, extracellular Ca2+ de
creased to virtually 0 mmol/L, and 250-miIIisecond depolarizing pulse
to -20 mV). In contrast, triamterene had no effects on time-independen
t currents. Thus, data obtained indicate that triamterene, at clinical
ly relevant concentrations, inhibits I-Ks in a selective manner, altho
ugh both components of I-K (I-Kr and I-Ks) were decreased. This block
of I-K may explain triamterene-related prolongation of cardiac repolar
ization and warn about potential drug interaction with action potentia
l-prolonging agents.