Ionic mechanisms for the antiarrhythmic action of cinnamophilin in rat heart

Abstract

We investigated the electrophysiological effect and antiarrhythmic potential of cinnamophilin (Cinn), a thromboxane A(2) 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 microM 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 (APD(50)). Voltage clamp study showed that the suppression of V(max) by Cinn was associated with an inhibition of sodium inward current (I(Na), IC(50) = 10.0 +/- 0.4 microM). At 30 microM, 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 IC(50) value of 9.5 +/- 0.3 microM. Cinn (10 microM) reduced the I(Ca) with a negative shift of V(1/2) for the steady-state inactivation curve of I(Ca) from -32.2 +/- 0.3 to -50.7 +/- 0.4 mV. The prolongation of APD(50) was associated with an inhibition of the integral of potassium outward current with IC(50) values between 4.8 and 7.1 microM. At 10 microM, 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 microM) was associated with an acceleration of its time constant of inactivation and negative shift of its potential-dependent steady-state 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 microM. 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.

Electromechanical characterization of cinnamophilin, a natural thromboxane A2 receptor antagonist with anti‐arrhythmic activity, in guinea‐pig heart

“…Moreover, cinnamophilin was reported to protect ischaemic skeletal muscle from the reperfusion injury in rats ( Cheng and Chang, 1995 ) and to act as a novel antioxidant and cytoprotectant against oxidative damage ( Hsiao et al , 2001 ). In a recent study performed in isolated Langendorff‐perfused rat heart, cinnamophilin was effective in the reduction of the coronary artery ligation/reperfusion‐induced arrhythmias ( Su et al , 1999 ). This profile of activity may be attributed to its electrophysiological actions such as blockade of the transient outward K + ( I to ), Na + and Ca 2+ channels ( Su et al , 1999 ).…”

“…In a recent study performed in isolated Langendorff‐perfused rat heart, cinnamophilin was effective in the reduction of the coronary artery ligation/reperfusion‐induced arrhythmias ( Su et al , 1999 ). This profile of activity may be attributed to its electrophysiological actions such as blockade of the transient outward K + ( I to ), Na + and Ca 2+ channels ( Su et al , 1999 ).…”

“…The cardiac action potential waveforms differ between animal species, owing to differences in ion channel expression ( Nerbonne and Kass, 2005 ). Evidence indicates that cinnamophilin caused a significant prolongation of rat cardiac action potential ( Su et al , 1999 ) which displays a prominent phase 1 repolarization and a brief plateau occurs at more negative potentials ( Josephson et al , 1984 ). The class III anti‐arrhythmic agent‐like property is mainly due to the blockade of the I to ( Su et al , 1999 ) which is the most important repolarizing current in rat heart ( Josephson et al , 1984 ).…”

Biomedical vignette

“…Reentry and oscillatory after potential are two mechanisms proposed to be responsible tor the induced arrhythmia [14]. Based on studies on rat cardiac tissues, Suet al [16] reported that cinnamophilin, a thromboxane A 2 antagonist isolated from Cinnamomum philippinense, exerts antiarrhythmic activity by prolonging the duration and inhibiting the upstroke of action potential. They further showed that inhibition of sodium, caldum and transient outward potassium currents may underlie the observed antiarrhythmic actions.…”

Biomedical Vignette

“…Reentry and oscillatory after potential are two mechanisms proposed to be responsible for the induced arrhythmia [14]. Based on studies on rat cardiac tissues, Su et al [16] reported that cinnamophilin, a thromboxane A 2 antagonist isolated from Cinnamomum philippinense, exerts antiarrhythmic activity by prolonging the duration and inhibiting the upstroke of action potential. They further showed that inhibition of sodium, calcium and transient outward potassium currents may underlie the observed antiarrhythmic actions.…”