5-Hydroxytryptamine antagonist ICS 205-930 blocks cardiac potassium, sodium and calcium currents.
Effects of the 5-hydroxytryptamine receptor antagonist ICS 205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester] on cardiac membrane currents were investigated in single isolated ventricular cells using the whole-cell patch clamp method. Ca++ and K+ currents were studied in guinea pig ventricular cells and Na+ currents were studied in ventricular cells from cultured neonatal rat; these cells are more suitable for Na+ current measurements than are ventricular cells from guinea pig. Under current clamp conditions, ICS 205-930 at 3 x 10(-5) M prolonged the action potential plateau and increased its amplitude of guinea pig cell. The effect was reversible. Increasing the concentration to 3 x 10(-4) M shortened the plateau, reduced its amplitude and depolarized the resting membrane potential. The effects between 10(-7) and 10(-3) M were examined under voltage-clamp conditions. ICS 205-930 produced a concentration-dependent suppression of inwardly rectifying K+ currents with an IC50 of 1.95 x 10(-5) M at a test potential of -40 mV. The effects were time-and voltage-dependent and the IC50 increased to 1.16 x 10(-4) M at -100 mV. The time-dependent outward current and the time-dependent outward tail currents upon repolarization to between -10 and -30 mV also were blocked by the drug in a concentration-dependent manner with IC50 of 3.7 x 10(-5) M. Ca++ currents and Na+ currents also were inhibited in the presence of higher concentration of ICS 205-930 (greater than 10(-4) M), although potency was stronger on Na+ currents. The results show that ICS 205-930 exerts mixed class III and class I antiarrhythmic properties in ventricular myocytes.
Scholtysik
G
G
Department of Physiology and Molecular Biophysics, Baylor College of Medicine, Texas Medical Center, Houston.
Imoto
Y
Y
Yatani
A
A
Brown
A M
AM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D000077526:Tropisetron
D000889:Anti-Arrhythmia Agents; D007211:Indoles; D007473:Ion Channels; D012702:Serotonin Antagonists; D000077526:Tropisetron; D012964:Sodium; D011188:Potassium; D002118:Calcium