The electrophysiological effects of antiarrhythmic potential of a secoaporphine, N‐allylsecoboldine

Wu, Mei‐Hwan; Su, Meiying; Lee, Shoei‐Sheng; Young, Ming‐Lon

doi:10.1111/j.1476-5381.1994.tb16197.x

Cited by 22 publications

(12 citation statements)

References 26 publications

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“…These results suggest that Cinn may exert antiarrhythmic activity by a mode of action similar to class I, III and IV antiarrhythmic agents. The potency of antiarrhythmic activity is comparable to some natural alkaloids such as (-)-caryachine [43] but weaker than N-allylsecoboldine [41] and liriodenine [6].…”

Section: Discussionmentioning

confidence: 68%

Ionic Mechanisms for the Antiarrhythmic Action of Cinnamophilin in Rat Heart

Chen

et al. 1999

J Biomed Sci

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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 I_Ca 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 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 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.

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Section: Discussionmentioning

confidence: 68%

Ionic Mechanisms for the Antiarrhythmic Action of Cinnamophilin in Rat Heart

Chen

et al. 1999

J Biomed Sci

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“…Na currents were decreased but the threshold potential and the potential at which the maximal Na current was recorded remained unchanged. a Cardiac myocytes were isolated as previously described (Mitra & Morad, 1985;Wu et al, 1994a). Ionic currents were studied in whole-cell configuration at room temperature (25 -270C) (Hamill et al, 1981).…”

Section: Methodsmentioning

confidence: 99%

“…Animal preparation The heart including part of the superior and inferior vena cava was excised via thoractomy and the aorta was retrogradely perfused (Young et al, 1989;Wu et al, 1994a). A tungsten wire soldered to a silver-wire bipolar electrode was placed on an area near the apex of the triangle of Kochs to record the His bundle electrograms (HBE).…”

Section: Intracardiac Electrocardiogram Recordingmentioning

confidence: 99%

“…By using large-scale screening tests and electrophysiological studies, some derivatives of these medicinal plants have been shown to be promising antiarrhythmic, or positive inotropic agents (Su et al, 1993;Young et al, 1994;Wu et al, 1994a). During one such large-scale screening test, (-)-caryachine, a compound isolated from natural plant (Cryptocarya chinensis) (Figure la) (Lu & Lan, 1966), mol.wt.…”

Section: Introductionmentioning

confidence: 99%

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Electrophysiological basis for antiarrhythmic efficacy, positive inotropy and low proarrhythmic potential of (—)‐caryachine

Lee

et al. 1995

British J Pharmacology

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1 (-)-Caryachine, isolated from the plant (Cryptocarya chinensis), increased the contractility of atrial and right ventricular strips and significantly suppressed the reperfusion arrhythmias in adult rabbit heart (ED50= 1.27 gM).2 Data obtained by the whole-cell voltage clamp technique has shown that (-)-caryachine causes a negative shift of the steady-state Na channel inactivation and a slower rate of recovery from inactivation. The maximal Na current amplitude decreased to 67+7%, 29+8% and 12+5% after 0.5, 1.5 and 4.5 gM (-)-caryachine, respectively. 3 This agent also had effects on the time-and voltage-dependent K currents. (-)-Caryachine markedly suppressed the 4-AP-sensitive transient outward current (Ito). However, it produced very little voltagedependent shift in inactivation. After 0.5, 1.5 and 4.5 gM of the compound, the respective value of Ito elicited at + 60 mV was 80 + 7%, 45 + 8% and 15 + 3%. At higher concentrations, the inward rectifier K current (IKC) was also inhibited but to a much smaller extent. Its slope conductance after 0.5, 1.5 and 4.5 Mm (-)-caryachine was reduced to 71+9%, 51 + 12% and 42+11%, respectively. The outward hump of inward rectification was not changed. 4 In contrast, the L-type Ca current was not significantly changed by (-)-caryachine. 5 Electrophysiological studies in perfused whole heart preparations revealed that (-)-caryachine increased the intra-atrial conduction interval and also prolonged the atrial refractory period. No proarrhythmic effects were induced during the infusion of this compound (up to 13.5 gM). 6 We conclude that (-)-caryachine predominantly blocks the Na and Ito currents. These changes alter the electrophysiological properties of the heart and terminate the induced ventricular arrhythmias. The relatively selective Ito inhibition, safety margin of IKI suppression and lack of effect on ICa-L will provide an opportunity to develop an effective antiarrhythmic agent with positive inotropy as well as low proarrhythmic potential.

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“…Our methods have been described elsewhere (12), but in brief, the heart was excised via thoracotomy, and the aorta was retrogradely perfused. For pacing the atria, a high right atrial electrode was placed near the junction of the superior vena cava and the right atrium.…”

Section: Intracardiac Ecg Recordingmentioning

confidence: 99%

Age-Related Differences in the Direct Cardiac Effects of Cisapride: Narrower Safety Range in the Hearts of Young Rabbits

Sun

2003

Pediatr Res

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Although cisapride is widely used to treat gastrointestinal motility disorders, it has been associated with QT prolongation, torsades de pointes, and cardiac arrest. Only in children, however, has atrioventricular (AV) block after cisapride been reported. This study used Langendorff perfusion to determine the direct effects of cisapride (0.03, 0.1, 0.3, and 1 M) on the conduction properties of neonatal (Ͻ7 d) and adult (Ͼ3 mo) rabbit hearts. At a clinically relevant dose (0.03 M), cisapride slowed the recovery of the His-Purkinje system. At 0.1 M, the refractoriness of the His-Purkinje system and conduction through this system were prolonged. Corrected QT intervals and the ventricular refractory period were also lengthened. These parameters were significantly more prolonged in neonates than in adults. The level of AV block at rapid atrial pacing shifted from the AV node to the His-Purkinje system, with an ED 50 of 0.06 and 0.52 M in the neonate and the adult, respectively. In the neonate, cisapride even resulted in infranodal AV block rhythm (ED50 ϭ 0.12 M), but this was not the case in the adult. Polymorphic ventricular tachycardia after cisapride was induced in one in seven neonates (14%;, 0.1 M) and in one in seven adults (14%; 0.03 M). It is concluded that cisapride may affect the refractoriness of cardiac tissue and that the His-Purkinje system seems to be the most sensitive. In neonatal hearts, this modification may, in fact, progress to infranodal AV block. Such susceptibility to cisapride strongly indicates that the therapeutic safety range used for the young heart should be narrowed. Cisapride, a widely used gastrointestinal prokinetic agent, has been associated with the development of prolonged QT interval, malignant ventricular arrhythmias, and sudden death (1, 2). Cisapride is a gastrointestinal prokinetic agent that facilitates gastrointestinal motility by increasing lower esophageal sphincter pressure and improving gastric emptying (3). The mechanism of such gastrointestinal action is attributable to an enhanced release of acetylcholine at the mesenteric plexus as well as a direct suppression of human ether-a-go-go-related gene (HERG)-like K ϩ currents in the esophageal smooth muscle (4, 5). As for the mechanisms underlying the adverse cardiac effects, a direct inhibition of the repolarizing K ϩ current and the subsequent prolongation of action potential have previously been suggested. In rabbit Purkinje fibers, cisapride (0.1-10 M) lengthened the action potential duration in a concentration-dependent and reverse rate-dependent manner, and early after-depolarizations with the succeeding triggered activity were observed at abruptly decelerating pacing rates (6). Apart from this, in isolated rabbit myocytes, the rapid component of the delayed rectifying K ϩ current (I Kr ) was blocked by cisapride with an IC 50 of 9 nM (7).In the immature heart, the presence of age-related differences in the K ϩ repolarizing currents has been well documented (8, 9), but whether these differences make immature hearts ...

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The electrophysiological effects of antiarrhythmic potential of a secoaporphine, N‐allylsecoboldine

Cited by 22 publications

References 26 publications

Ionic Mechanisms for the Antiarrhythmic Action of Cinnamophilin in Rat Heart

Ionic Mechanisms for the Antiarrhythmic Action of Cinnamophilin in Rat Heart

Electrophysiological basis for antiarrhythmic efficacy, positive inotropy and low proarrhythmic potential of (—)‐caryachine

Age-Related Differences in the Direct Cardiac Effects of Cisapride: Narrower Safety Range in the Hearts of Young Rabbits

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