Comparison of the electrophysiological effects of S49, CSH087 and CSH068 in rat ventricular cells.
S49, CSH087 and CSH068 are aporphine alkaloids and are synthesized from vanillin. In the present study, the effects of these compounds on the action potential and membrane currents of rat ventricular cells were examined by using the whole cell recording technique with single suction pipettes. At a stimulation frequency of 0.1 Hz, S49 (1.5 microM), CSH087 (3 microM) and CSH068 (3 microM) could prolong the action potential durations (APD50 and APD90). Voltage clamp studies revealed inhibition of the transient outward currents by S49, CSH087 and CSH068 with KD of 2.0, 1.8 and 5.2 microM, respectively, but a lack of enhancement of calcium influx. Therefore, the inhibition of the potassium conductance may explain the prolongation of APD induced by these compounds. In contrast, the late potassium outward current was more resistant to CSH087 and S49, but was blocked by CSH068 with a KD of 6.4 microM. The sodium inward current (INa) also was inhibited by S49, CSH087 and CSH068 in a dose-dependent manner with KD of 1.2, 6.8 and 7.5 microM, respectively (at a holding potential of -80 mV). The inhibition of INa) was enhanced at a less negative holding potential. The voltage-dependent inhibition of INa was associated with the shift of the INa availability curve to more negative potentials. These results indicate that these compounds have high affinity for inactivated Na+ channels. A twin-pulse experiment revealed that these compounds increased the recovery time constant of INa. The potency for the shift of the INa availability curve and the retardation of INa recovery from inactivation were S49 > CSH087 and CSH)68.(ABSTRACT TRUNCATED AT 250 WORDS)
Chen
L
L
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Republic of China.
Lee
C S
CS
Su
M J
MJ
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D044005:Tetrahydroisoquinolines; D013997:Time Factors
D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D007473:Ion Channels; D007546:Isoquinolines; D015221:Potassium Channels; D015222:Sodium Channels; D044005:Tetrahydroisoquinolines; C084926:CSH 068; C084925:CSH 087; C084924:1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline