A new class III antiarrhythmic drug, MS-551, blocks the inward rectifier potassium channel in isolated guinea pig ventricular myocytes.
We have studied the effects of MS-551 on the inward rectifier potassium channel (IK1) in isolated guinea-pig ventricular myocytes by use of whole-cell and single-channel recording techniques. MS-551 (5 microM) blocked the IK1 current. The percent blockade of the peak and steady-state IK1 current by MS-551 was constant at each test potential. In contrast 50 microM MS-551 failed to block either the sodium or the calcium current. Under cell-attached patch conditions, MS-551 reduced the open probability of IK1 channel activity by prolonging the interburst interval without changing either the unitary amplitude or the equilibrium potential. The blockade of IK1 was concentration-dependent. MS-551 did not change either the mean open time or mean closed time within a burst. Extracellular acidification (pH 6.4) strongly attenuated the effect of MS-551 on the open probability of IK1 channel activity when compared with its effect at pH 7.4. In summary, our results demonstrated that MS-551 blocked the IK1 channel. The neutral form of this drug molecules may penetrate the cardiac cell membrane via a hydrophobic pathway to block the steady-state IK1 current by reduction of open probability.
Sato
R
R
First Department of Internal Medicine, Kinki University, Osaka, Japan.
Koumi
S
S
Hisatome
I
I
Takai
H
H
Aida
Y
Y
Oyaizu
M
M
Karasaki
S
S
Mashiba
H
H
Katori
R
R
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008564:Membrane Potentials; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011744:Pyrimidinones / Q000494:pharmacology*; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011744:Pyrimidinones; C076259:nifekalant