Inhibitory effects of dauricine on early afterdepolarizations and L-type calcium current.
We have previously reported that dauricine exerted antiarrhythmic effects on various experimental arrhythmias. To further clarify its mechanism, the effects of dauricine on action potential duration (APD), early afterdepolarizations (EADs), triangulation, which is defined as the repolarization time from APD at 30% level (APD30) to APD at 90% level (APD90), and L-type calcium current (I(Ca-L)) were studied using standard microelectrode techniques on rabbit papillary muscles and whole-cell patch clamp techniques on single myocytes isolated from rabbits by enzymatic digestion, respectively. Cardiac hypertrophy was induced by coarctating the abdominal aorta of rabbits. The results showed that in papillary muscles of hypertrophied rabbits, 1 micromol/L dofetilide, a selective IKr blocker, prolonged APD50 and APD90 and induced EADs (4/6, p < 0.01) with hypokalemia ([K+]o = 2.7 mmol/L). Dauricine inhibited EADs (p < 0.01) and shortened the prolonged APD (p < 0.01). In single myocytes, dauricine also inhibited EADs induced by dofetilide, hypokalemia, and hypomagnesaemia. Dauricine decreased the triangulation and reduced the peak amplitude of I(Ca-L) at all potentials tested. Dauricine shifted the steady-state activation curves to the right and steady-state inactivation curves to the left and prolonged the tau value of the recovery curve. These results suggest that dauricine inhibits EADs and this effect may be associated with its blockade of I(Ca-L).
Liu
Qiang-Ni
QN
Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Zhang
Li
L
Gong
Pei-Li
PL
Yang
Xiao-Yan
XY
Zeng
Fan-Dian
FD
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced; D008274:Magnesium / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009467:Neuromuscular Depolarizing Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; C035934:dauricine; D008274:Magnesium; C063533:dofetilide; D011188:Potassium