Ionic mechanisms for the antiarrhythmic action of Cinnamophilin in rat heart

We investigated the electrophysiological effect and antiarrhythmic potential of cinnamophilin (Cinn), a thromboxane A₂ antagonist isolated from Cinnamomum philippinense, on rat cardiac tissues. Action potential and ionic currents in single rat ventricular cells were examined by current clamp or voltage clamp in a whole-cell configuration. In 9 episodes of ischemia- reperfusion arrhythmia, 10 μM Cinn converted 6 of them to normal sinus rhythm. Cinn suppressed the maximal rate of rise of the action potential upstroke (V(max)) and prolonged the action potential duration at 50% repolarization (APD₅₀). Voltage clamp study showed that the suppression of V(max) by Cinn was associated with an inhibition of sodium inward current (I(Na), IC₅₀ = 10.0 ± 0.4 μM). At 30 μM, V(1/2) for the steady-state inactivation curve of I(Na) was shifted from -84.1 ± 0.2 to -93.0 ± 0.5 mV. Cinn also reduced calcium inward current (I(Ca)) dose-dependently with an IC₅₀ value of 9.5 ± 0.3 μM. Cinn (10 μM) reduced the I(Ca) with a negative shift of V(1/2) for the steady-state inactivation curve of Ica from -32.2 ± 0.3 to -50.7 ± 0.4 mV. The prolongation of APD₅₀ was associated with an inhibition of the integral of potassium outward current with IC₅₀ values between 4.8 and 7.1 μM. At 10 μM, Cinn reduced I(Na) without a negative shift of its voltage-dependent steady-state inactivation curves. The inhibition of transient outward current (I(to)) by Cinn (3-30 μM) was associated with an acceleration of its time constant of inactivation and negative shift of its potential-dependent steadystate inactivation curves. The equilibrium dissociation constant (K(d)) of Cinn to inhibit open state I(to) channels, as calculated from the time constant of developing block, was 18.3 μM. The time constant of recovery of I(to) from inactivation state was unaffected by Cinn. The rate constant for the relief from the depolarization-dependent block of I(to) was calculated to be 23.9 ms. As compared with its effect on I(to), Cinn exerted about half the potency to block I(Na) and I(Ca). These results indicate that the inhibition of I(Na), I(Ca) and I(to) may contribute to the antiarrhythmic activity of Cinn against ischemia-reperfusion arrhythmia.