Trapidil enhances the slowly activating delayed rectifier potassium current and suppresses the transient inward current induced by catecholamine in Guinea pig ventricular myocytes.
We examined the electrophysiological effects of trapidil on the ionic currents influencing the repolarization and on the transient inward current (ITi) that can cause triggered arrhythmia using the whole-cell patch-clamp technique in guinea pig ventricular myocytes. Trapidil shortened the action potential duration (APD) and increased the delayed rectifier potassium current (IK) in a concentration-dependent manner. The effect of trapidil on the rapidly and slowly activating components of IK (IKr and IKs, respectively) was studied by the envelope of tails test. Trapidil failed to affect IKr and selectively enhanced IKs. Trapidil increased the amplitude of the L-type Ca2+ current (ICa,L), with an acceleration of its inactivation, whereas isoproterenol, a beta-adrenoceptor agonist, increased the amplitude of the ICa,L in a different manner. Isoproterenol activated ITi; however, trapidil not only failed to facilitate ITi but also suppressed isoproterenol-induced ITi. The inhibitory effect of trapidil on isoproterenol-induced ITi is at least partly via a reduction of Ca2+ overload through an acceleration of ICa,L inactivation and/or a sarcoplasmic reticulum (SR) Ca channel modulation. These results suggest that trapidil does not prolong the QT interval and has an antiarrhythmic effect on arrhythmias elicited by triggered activity secondary to Ca2+ overload at much higher concentrations than clinical concentration.
Marumoto
Akira
A
Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, Faculty of Medicine, Tottori University, Yonago, Japan.
Hasegawa
Junichi
J
Zhang
Fang
F
Moritani
Hisato
H
Harada
Tomomi
T
Sano
Akiko
A
Miura
Norimasa
N
Kishimoto
Yosuke
Y
Ohgi
Shigetsugu
S
D000200:Action Potentials / Q000187:drug effects*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002395:Catecholamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D012433:Ryanodine / Q000494:pharmacology; D014192:Trapidil / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D002395:Catecholamines; D024661:Potassium Channels, Inwardly Rectifying; D012433:Ryanodine; D014192:Trapidil; D007545:Isoproterenol; D011188:Potassium