LY-97241 ACCELERATES THE APPARENT RATE OF INACTIVATION OF TRANSIENT OUTWARD K+ CURRENT - CHARACTERIZATION OF OPEN-CHANNEL BLOCK

LY 97241 [(LY), p-nitro tertiary amine analog of clofilium] has been shown to prolong action potential duration in vitro but its effects on transient outward potassium current (I-to) are unknown. The authors investigated the effect of LY on I-to in rat ventricular myocytes using whole cell patch clamp techniques. LY resulted in a concentration-dependent inhibition of I-to amplitude (measured 30 msec after onset of depolarization) with an EC(50) of 5.85 mu M. The inhibitory effect of LY (10 mu M) was seen at voltages from -30 to 70 mV (e.g., at 30 mV, LY reduced amplitude from a control of 7.29 +/- 0.30 to 3.05 +/- 0.22 pA/pF, P < .01,n = 10). The voltage-dependent block by LY was fitted by the Boltzmann equation, yielding a voltage for half-maximal block (V-1/2) of -25.0 mV with a slope factor (k) of 13.8 mV. LY (10 mu M) accelerated the rate of I-to inactivation from 41.9 +/- 3.5 to 16.0 +/- 1.6 msec without an effect on the peak of I-to (n = 10, P < .01). In contrast, 4-aminopyridine (4-AP, 1 mM) had no effect on the rate of inactivation but decreased the peak of I-to from 1.84 +/- 1.6 to 0.71 +/- 0.20 nA (n = 3). The time constant of onset of block (tau(B)) on I-to by 10 mu M LY was fitted to a monoexponential function having a tau(B) of 14.5 +/- 1.5 msec. LY had no effect on the steady-state inactivation or recovery from inactivation of I-to. It was concluded that 1) LY prolongation of action potential duration, like the effect of 4-AP, may be mediated at least partly through inhibition of I-to and 2) LY differs from 4-AP by exerting an open channel block on I-to.