Effects of a novel cardioprotective drug, JTV-519, on membrane currents of guinea pig ventricular myocytes.
We investigated effects of a novel cardioprotective drug, JTV-519 (4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahy dro-1,4-benzothiazepine monohydrochloride) on membrane currents of guinea pig ventricular myocytes by whole-cell voltage and current clamp methods. The fast Na+ current (iNa) was activated by ramp pulses from various holding potentials of -90, -80 or -60 mV to 10 mV with various intervals. At 0.2 Hz, JTV-519 inhibited iNa in a concentration-dependent manner with an IC50 of approximately 1.2 and 2 microM at the holding potential of -60 and -90 mM, respectively, implicating a voltage-dependent block. Increasing the pulse frequency from 1 to 2 or 3.3 Hz in the presence of 1 microM JTV-519 shortened the time-course and increased the level of iNa block, indicating a frequency-dependent block. The time-course of iNa blocking by JTV-519 was slower than that of lidocaine and similar to that of quinidine. Ca2+ current (iCa) and the inwardly rectifying K+ current (iK1) were also inhibited by JTV-519. JTV-519 decreased the duration and the height of the plateau of the action potential. We conclude that JTV-519 has frequency- and voltage-dependent blocking effects on iNa as well as inhibition of iCa and iK1.
Kimura
J
J
Department of Pharmacology, School of Medicine, Fukushima Medical University, Japan.
Kawahara
M
M
Sakai
E
E
Yatabe
J
J
Nakanishi
H
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects; D013841:Thiazepines / Q000494:pharmacology*; D013997:Time Factors; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002317:Cardiovascular Agents; D015221:Potassium Channels; D015222:Sodium Channels; D013841:Thiazepines; C109183:K201 compound; D008012:Lidocaine; D011802:Quinidine