title: LY 97241 accelerates the apparent rate of inactivation of transient outward K+ current: characterization of open channel block.
abstract: 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 (Ito) are unknown. The authors investigated the effect of LY on Ito in rat ventricular myocytes using whole cell patch clamp techniques. LY resulted in a concentration-dependent inhibition of Ito amplitude (measured 30 msec after onset of depolarization) with an EC50 of 5.85 microM. The inhibitory effect of LY (10 microM) 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 (V1/2) of -25.0 mV with a slope factor (k) of 13.8 mV. LY (10 microM) accelerated the rate of Ito inactivation from 41.9 +/- 3.5 to 16.0 +/- 1.6 msec without an effect on the peak of Ito (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 Ito from 1.84 +/- 1.6 to 0.71 +/- 0.20 nA (n = 3). The time constant of onset of block (tau B) on Ito by 10 microM 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 Ito.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Lilly Research Laboratory, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
authors.forename: Z H
authors.initials: ZH
authors.lastname: Zhang
authors.forename: M I
authors.initials: MI
authors.lastname: Steinberg
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000644:Quaternary Ammonium Compounds; C056528:LY 97241; D015761:4-Aminopyridine; D011188:Potassium