Thaliporphine, a positive inotropic agent with a negative chronotropic action

Su, Ming‐Jai; Chang, Yu‐Mei; Chi, Jo-Feng; Lee, Shoei‐Sheng

doi:10.1016/0014-2999(94)90381-6

Cited by 29 publications

(21 citation statements)

References 31 publications

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“…In a large scale screening test, several aporphine alkaloids were isolated and found to be active in the cardiovascular system (Teng et al, 1991;Su et al, 1994;Young et al, 1994). Recently, we found that liriodenine (Figure 1), an aporphine derivative isolated from the plant Fissistigma glaucescens, possessed selective M3 muscarinic receptor antagonistic activity in guinea-pigs (Lin et al, 1994a) and in canine tracheal smooth muscle cells (Lin et al, 1994b).…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens

Chang

et al. 1996

British J Pharmacology

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1 The antiarrhythmic potential and electromechanical effects of liriodenine, an aporphine alkaloid isolated from the plant, Fissistigma glaucescens, were examined. 2 In the Langendorff perfused (with constant pressure) rat heart, at a concentration of 0.3 to 3 gM, liriodenine was able to convert a polymorphic ventricular tachyrhythmia induced by the ischaemiareperfusion (EC50 = 0.3 gM).3 In isolated atrial and ventricular muscle, liriodenine increased the contractile force and slowed the spontaneous beating of the right atrium.4 The liriodenine-induced positive inotropy was markedly attenuated by a transient outward K+ channel blocker, 4-aminopyridine (4-AP) but was not significantly affected by prazosin, propranolol, verapamil or carbachol. 5 In rat isolated ventricular myocytes, liriodenine prolonged action potential duration and decreased the maximal upstroke velocity of phase 0 depolarization (7,,ma) and resting membrane potential in a concentration-dependent manner. The action potential amplitude was not significantly changed. 6 Whole-cell voltage clamp study revealed that liriodenine blocked the Na+ channel (INa) concentration-dependently (IC50 = 0.7 gM) and caused a leftward shift of its steady-state inactivation curve. However, its recovery rate from the inactivated state was not affected. The L-type Ca2" currents (ICa) were also decreased, but to a lesser degree (ICo = 2.5 gM, maximal inhibition = 35%). 7 Liriodenine inhibited the 4-AP-sensitive transient outward current (I,.) (IC50 = 2.8 gM) and moderately accelerated its rate of decay. The block of Ito was not associated with changes in the voltage-dependence of the steady-state inactivation curve or in the process of recovery from inactivation of the current. Liriodenine also reduced the amplitude of a slowly inactivating, steady-state outward current (ISS) (IC50 = 1.9 ,M). These effects were consistent with its prolonging effect on action potential duration. The inwardly rectifying background K+ current (IK1), was also decreased but to a less degree. 8 Compared to quinidine, liriodenine exerted a stronger degree of block on INa, comparable degree of block on IKi, and lesser extent of block on ICa and In,. 9 It is concluded that, through inhibition of Na+ and the Ito channel, liriodenine can suppress ventricular arrhythmias induced by myocardial ischaemia reperfusion. The positive inotropic effect can be explained by inhibition of the Ito channel and the subsequent prolongation of action potential duration. These results provide a satisfactory therapeutic potential for the treatment of cardiac arrhythmias.

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Section: Introductionmentioning

confidence: 99%

Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens

Chang

et al. 1996

British J Pharmacology

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“…Among them, many alkaloids were found to have vasorelaxing [12,38,39] or antiarrhythmic activities [23, 40-42, 44, 48]. Consistent with their antiarrhythmic activities, electrophysiological studies revealed that these agents block cardiac Na + channels [35,36,45] and prolong the duration of action potential by inhibition of potassium outward currents [18,33,35,36,43].…”

Section: Introductionmentioning

confidence: 92%

“…The suppression of V max was manifested by the inhibition of sodium channels. These results suggest that Cinn may exert antiarrhythmic activity by suppression of oscillatory afterpotentials or extrasystole via blocking the sodium channels like most of the natural alkaloids [6,35,36,41,43] and class I antiarrhythmic agents [1,8,9,16,20,22,32,34,42]. The prolongation of APD by agents such as tedisamil, which was known to inhibit I to [13,14], could reduce the incidence of ischemia-induced ventricular fibrillation or decrease the duration of reperfusion-induced ventricular fibrillation [3].…”

Section: Mechanism Of Antiarrhythmic Action Of Cinnmentioning

confidence: 99%

“…Use-dependent inhibition of I Na , retardation of recovery of Na + channels from their inactivation state and negative shift of the voltage-dependent inactivation curve of I Na are major mechanisms responsible for the action of most agents with class I antiarrhythmic activity [1,8,9,20,22,30,32,[34][35][36][41][42][43]. Since 10 ÌM Cinn reduced I Na without negative shift of V 1/2 for the steady-state inactivation curves of I Na , the inhibition of I Na by Cinn at concentrations lower than 10 ÌM may be due to its binding to sodium channels in resting or open state.…”

Section: Discussionmentioning

confidence: 99%

“…This finding suggests that the inhibition of I to by Cinn cannot be explained solely by its binding to open channels. A stronger open-channel blocking activity of I to by quinidine, propafenone and other natural alkaloids with K d values less than 10 ÌM was reported [7,19,29,35,36].…”

Section: Analysis Of the Mode Of Action Of Cinn On I Tomentioning

confidence: 99%

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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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Thaliporphine protects ischemic and ischemic‐reperfused rat hearts via an NO‐dependent mechanism

Hung

Lee

Chen

et al. 2001

Drug Development Research

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In ischemia or ischemia-reperfusion (I/R), nitric oxide (NO) can potentially exert several beneficial effects. Thaliporphine, a natural alkaloid with Ca 2+ channel-activating and Na + /K + channel-blocking activities, increased NO levels and exerted cardioprotective action in ischemic or I/R rats. The role of NO in the cardioprotective actions of thaliporphine was assessed. The severity of rhythm disturbances and mortality in anesthetized rats with either coronary artery occlusion for 30 min, or 5 min followed by 30-min reperfusion, were monitored and compared in thaliporphine-vs. placebo-treated groups. Thaliporphine treatment significantly increased NO and decreased lactate dehydrogenase (LDH) levels in the blood during the end period of ischemia or I/R. These changes in NO and LDH levels by thaliporphine were associated with a reduction in the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischemic or I/R period. The mortality of animals was also completely prevented by 1 × 10 -8 moles/kg of thaliporphine. In animals subjected to 4 h of left coronary artery occlusion, 1 × 10 -7 moles/kg of thaliporphine dramatic reduced cardiac infarct zone from 46 ± 6% to 7.1 ± 1.9%. Inhibition of NO synthesis with 3.7 × 10 -6 moles/kg of N ω -nitro-L-arginine methyl ester (L-NAME) abolished the beneficial effects of thaliporphine during 30 min or 4 h myocardial ischemia. However, the antiarrhythmic activity and mortality reduction efficacy of thaliporphine during reperfusion after 5 min of ischemia was only partially antagonized by L-NAME. These results showed that thaliporphine efficiently exerted the cardioprotections either in acute or prolonged coronary artery occlusion or occlusion-reperfusion situations. The fact that thaliporphine induced cardioprotective effects were abrogated by L-NAME indicates that NO is an important mediator for the cardioprotective effects of thaliporphine in acute or prolonged ischemia, whereas antioxidant activities may contribute to the protection of I/R injury. Drug Dev. Res. 52:446-453, 2001.

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Thaliporphine, a positive inotropic agent with a negative chronotropic action

Cited by 29 publications

References 31 publications

Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens

Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens

Ionic Mechanisms for the Antiarrhythmic Action of Cinnamophilin in Rat Heart

Thaliporphine protects ischemic and ischemic‐reperfused rat hearts via an NO‐dependent mechanism

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