Modulation by muscarinic receptor antagonists on negative chronotropic effects of tetrandrine.
OBJECTIVE
To investigate the influence of selective antagonist for muscarinic (M) receptor subtype on tetrandrine (Tet) reducing heart rate, inhibiting sinoatrial node (SAN) function, and its ionic mechanism.


METHODS
Effects of reducing heart rate of Tet were maintained in isolated right atrium and pithed rats. Modification on action potentials (AP) of SAN cells and L-type calcium current (ICa-L) by Tet were recorded by means of standard microelectrode and patch-clamp whole cell recording techniques.


RESULTS
Tet inhibited spontaneous beating rate of isolated right atrium (EC50, 23.7 mumol.L-1) and reduced heart rates in pithed rats in a concentration-dependent manner (EC50, 18.6 mg.kg-1). Automaticity of SAN was inhibited by Tet. AP upstroke velocity (Vmax), spontaneous depolarization rates in phase 4 (SP4) were decreased and sinus cycle length (SCL) was prolonged when treated with Tet. Tet (30 mumol.L-1) caused a reduction in peak value of ICa-L from (1275 +/- 190) pA to (498 +/- 94) pA in isolated single cardiomyocyte. Atropine and AF-DX 116 (M2 subtype selective antagonist) could attenuate such effects of Tet in a competitive mode.


CONCLUSIONS
Negative chronotropic effects of Tet are due to its inhibition of ICa-L. Modification on ICa-L is the major mechanism of M receptor modulating Tet effects.
Zhong
N
N
Department of Pharmacology, Tongji Medical University, Wuhan 430030, China.
Qian
J Q
JQ
D000200:Action Potentials / Q000187:drug effects; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology*; D044182:Benzylisoquinolines; D015220:Calcium Channels / Q000187:drug effects; D003864:Depression, Chemical; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012849:Sinoatrial Node / Q000502:physiology
D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D044182:Benzylisoquinolines; D015220:Calcium Channels; D018727:Muscarinic Antagonists; C009438:tetrandrine; D010890:Pirenzepine; D001285:Atropine; C048593:otenzepad