5-HYDROXYTRYPTAMINE ANTAGONIST ICS-205-930 BLOCKS CARDIAC POTASSIUM, SODIUM AND CALCIUM CURRENTS

  • 1 June 1988
    • journal article
    • research article
    • Vol. 245  (3) , 773-778
Abstract
Effects of the 5-hydroxytryptamine3 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 .times. 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 .times. 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 .times. 10-5 M at a test potential of -40 mV. The effects were time- and voltage-dependent and the IC50 increased to 1.16 .times. 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 .times. 10-5 M. Ca++ currents and Na+ currents also were inhibited in the presence of higher concentration of ICS 205-930 (>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.