ryanodine and tetrandrine

The effect of tetrandrine on the electrically induced elevation of cytosolic Ca2+ concentration, [Ca2+]i, in the single isolated rat cardiomyocyte was studied with a fluorometric ratio method using fura-2 acetomethylester (fura-2/AM) was Ca2+ indicator. Tetrandrine (3-100 microM) concentration and time dependently inhibited the amplitude of the [Ca2+]i transient without any significant effect on the resting level of [Ca2+]i. At high concentrations (60-100 microM), tetrandrine also prolonged the time to reach the peak (t1.0) and the time to decline the 20% of the peak level (t0.2) of the electrically induced [Ca2+]i transient. The effect of tetrandrine was fast in onset and fully reversible upon washout. Tetrandrine (10 microM) partially inhibited the elevation of [Ca2+]i in response to KCl-induced depolarization. Verapamil and diltiazem mimicked the effects of tetrandrine given at low concentrations, but not at high concentrations. At high concentrations, tetrandrine reduced the magnitude of the caffeine-induced [Ca2+]i transient. Tetrandrine (100 microM) administered after thapsigargin, which itself decreased the amplitude and prolonged the duration of the electrically induced [Ca2+]i transient, further decreased the amplitude of the [Ca2+]i elevation. After ryanodine, which itself decreased the amplitude of the [Ca2+]i transient, 100 microM tetrandrine not only further reduced the amplitude, but also prolonged the duration of the electrically induced [Ca2+]i transient. These results provide evidence that in addition to its inhibitory effect on Ca2+ influx at the sarcolemma at the therapeutically relevant concentrations, tetrandrine at high concentrations may inhibit Ca2+ uptake into the sarcoplasmic reticulum.

Topics: Alkaloids; Animals; Benzylisoquinolines; Caffeine; Calcium; Calcium Channel Blockers; Diltiazem; Electric Stimulation; Heart; In Vitro Techniques; Potassium Chloride; Rats; Rats, Sprague-Dawley; Ryanodine; Sodium; Thapsigargin; Verapamil