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Modulation by muscarinic receptor antagonists on negative chronotropic effects of tetrandrine
Aim:
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.
Conclusion:
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.