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 sin oatrial node (SAN) function, and its ionic mechanism. METHODS: Effects of r educing heart rare of Tet were maintained in isolated right atrium and pith ed rats. Modification on action potentials (AP) of SAN cells and L-type cal cium current (ICa-L) by Tet were recorded by means of standard microelectro de and patch-clamp whole cell recording techniques. RESULTS: Tel inhibited spontaneous beating rate of isolated right atrium (EC50, 23.7 mu mol.L-1) a nd 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 upstrok e velocity (V-max), spontaneous depolarization rates in phase 4 (SP4) were decreased and sinus cycle length (SCL) was prolonged when treated with Tet. Tet (30 mu mol.L-1) caused a reduction in peak value of ICa-L from (1275 /- 190) pA to (498 +/- 94) pA in isolated single cardiomyocyte. Atropine an d AF-DX 116 (M-2 subtype selective antagonist) could attenuate such effects of Tet in a competitive mode. CONCLUSION: Negative chronotropic effects of Ter are due to its inhibition of ICa-L. Modification on ICa-L is the major mechanism of M receptor modulating Tet effects.