Effects of ropinirole on action potential characteristics and the underlying ion currents in canine ventricular myocytes.
In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the dopamine receptor agonist ropinirole. In the present study, therefore, the concentration-dependent effects of ropinirole on action potential morphology and the underlying ion currents were studied in enzymatically dispersed canine ventricular cardiomyocytes using standard microelectrode, conventional whole-cell patch clamp, and action potential voltage clamp techniques. At concentrations > or = 1 microM, ropinirole increased action potential duration (APD(90)) and suppressed the rapid delayed rectifier K(+) current (I (Kr)) with an IC(50) value of 2.7 +/- 0.25 microM and Hill coefficient of 0.92 +/- 0.09. The block increased with increasing depolarizations to more positive voltages, but paradoxically, the activation of I (Kr) was accelerated by 3 muM ropinirole (time constant decreased from 34 +/- 4 to 14 +/- 1 ms). No significant changes in the fast and slow deactivation time constants were observed with ropinirole. At higher concentrations, ropinirole decreased the amplitude of early repolarization (at concentrations > or = 10 microM), reduced the maximum rate of depolarization and caused depression of the plateau (at concentrations > or = 30 microM), and shortened APD measured at 50% repolarization (at 300 microM) indicating a concentration-dependent inhibition of I (to), I (Na), and I (Ca). Suppression of I (Kr), I (to), and I (Ca) has been confirmed under conventional patch clamp and action potential voltage clamp conditions. I (Ks) and I (K1) were not influenced significantly by ropinirole at concentrations less than 300 microM. All these effects of ropinirole were fully reversible upon washout. The results indicate that ropinirole treatment may carry proarrhythmic risk for patients with inherited or acquired long QT syndrome due to inhibition of I (Kr)-especially in cases of accidental overdose or intoxication.
Simkó
József
J
Department of Cardiology, Institute of Medicine, Semmelweis Health Care Center, Miskolc, Hungary.
Szentandrássy
Norbert
N
Harmati
Gábor
G
Bárándi
László
L
Horváth
Balázs
B
Magyar
János
J
Bányász
Tamás
T
Lorincz
István
I
Nánási
Péter P
PP
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004285:Dogs; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques
D018491:Dopamine Agonists; D007211:Indoles; D007473:Ion Channels; C046649:ropinirole