Mechanical and electrophysiological effects of a hydroxyphenyl-substituted tetrahydroisoquinoline, SL-1, on isolated rat cardiac tissues

Chang, Gwo‐Jyh; Su, Meiying; Lee, Pei-Hong; Lee, Shoei‐Sheng; Liu, Karin Chiung-Sheue

doi:10.1139/y95-727

Cited by 4 publications

(2 citation statements)

References 22 publications

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“…The apparent increase in the rate of I to inactivation induced by HA-7 most probably reects block of open channels. Such I to inhibition is similar to that induced by quinidine , bupivacaine (Castle, 1990) and SL-1 (Chang et al, 1995). However, a drug-induced acceleration in the conversion of open channels to the inactivated state cannot be completely ruled out.…”

Section: Discussionmentioning

confidence: 61%

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA‐7, a furoquinoline alkaloid derivative, in rat heart

Chang

et al. 1997

British J Pharmacology

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1 HA-7, a new synthetic derivative of furoquinoline alkaloid, increased the contractile force of right ventricular strips and eectively suppressed the ischaemia-reperfusion induced polymorphic ventricular tachyrhythmias in adult rat heart (EC 50 =2.8 mM). 2 In rat ventricular myocytes, HA-7 concentration-dependently prolonged the action potential duration (APD) and decreased the maximal rate of rise of the action potential upstroke (V . max ). The action potential amplitude and resting membrane potential were also reduced, but to a smaller extent. The prolongation of APD by HA-7 was prevented by pretreating the cells with 1 mM 4-AP. 3 Voltage clamp experiments revealed that HA-7 decreased the maximal current amplitude of I Na (IC 50 =4.1 mM) and caused a negative shift of its steady-state inactivation curve and slowed its rate of recovery from inactivation. The use-dependent inhibition of I Na by HA-7 was enhanced at a higher stimulation rate. The L-type Ca 2+ current (I Ca ) was also reduced, but to a lesser degree (IC 50 =5.3 mM, maximal inhibition=31.8%). 4 This agent also in¯uenced the time-and voltage-dependent K + currents. The prolongation of APD was associated with an inhibition of a 4-AP sensitive transient outward K + current (I to ) (IC 50 =2.9 mM) and a slowly inactivating, steady-state outward current (I ss ) (IC 50 =2.5 mM). The inhibition of I to by HA-7 was associated with an acceleration of its time constant of inactivation. HA-7 suppressed I to in a time-dependent manner and caused a signi®cant negative shift of the voltage-dependent steady-state inactivation curve but did not aect its rate of recovery from inactivation. 5 At higher concentrations, the inward recti®er K + current (I K1 ) was also inhibited but to a less extent. Its slope conductance after 3, 10 and 30 mM HA-7 was decreased by 24+4%, 41+5% and 54+8%, respectively. 6 We conclude that HA-7 predominantly blocks I to and Na + channels and that it also weakly blocks Ca 2+ and I K1 channels. These changes alter the electrophysiological properties of the heart and terminate the ischaemia reperfusion induced ventricular arrhythmia. The signi®cant I to inhibition and minimal I Ca suppression may aord an opportunity to develop an eective antiarrhythmic agent linked with positive inotropy.

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Section: Discussionmentioning

confidence: 61%

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA‐7, a furoquinoline alkaloid derivative, in rat heart

Chang

et al. 1997

British J Pharmacology

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“…In view of the leftward shift of the I to inactivation curve and the failure to accelerate I to decay, (+)-MK801 may bind preferentially to inactivated I to channels instead of the open-state I to channels. This mode of inhibition of I to by (+)-MK801 is different from that by quinidine [16,32], bupivacaine [4], dicentrine [27], thaliporphine [26] and other alkaloids [5][6][7][8].…”

Section: Mode Of Channel Blocking Actions Of (+)-Mk801mentioning

confidence: 94%

Positive Inotropic Action of NMDA Receptor Antagonist (+)-MK801 in Rat Heart

Wang¹,

Su²

1999

J Biomed Sci

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(+)-MK801, a noncompetitive NMDA receptor antagonist, was reported to exhibit anticonvulsive and neuroprotective activities during the postischemic period. Intravenous administration of (+)-MK801 produced tachycardia in rats, but bradycardia in pigs. We examined the mechanical and electrophysiological effects of (+)-MK801 on rat cardiac tissues. (+)-MK801 dose-dependently increased (3–100 μM) twitch tension in rat atria and ventricular strips. The spontaneous beating rate in rat right atria, however, was dose-dependently decreased by (+)-MK801. The inotropic effect of (+)-MK801 was affected neither by α₁-antagonist (1 μM prazosin) nor by β₁-adrenoceptor antagonist (3 μM atenolol), but significantly by a transient outward K⁺ channel blocker (3 mM 4-aminopyridine). (+)-MK801 did not cause any significant change of intracellular cAMP content. Electrophysiological study in rat ventricular cells revealed that (+)-MK801 concentration-dependently prolonged the action potential duration with a concomitant decrease in the maximum rate of the action potential upstroke (V_max) and an increase in the recovery time constant of V_max. Voltage clamp study showed that (+)-MK801 (3 μM) reduced inward Na⁺ current (I_Na), along with a slowing of its recovery from inactivation and a slight negative shift of its voltage-dependent steady-state inactivation curves. At a much higher concentration (30 μM), (+)-MK801 slightly reduced the amplitude of L-type calcium inward current (I_Ca), although the voltage dependence of its steady-state inactivation was unaffected. For the potassium currents in rat ventricular cells, 3 μM of (+)-MK801 reduced the peak transient outward current (I_to), steady-state outward current (I_ss) and inward current through K₁ channels. The inhibition of I_to was associated with a prominent negative shift in the voltage dependence of its steady-state inactivation curve. The outward current through K₁ channels was unaffected. These results indicate that (+)-MK801 may be a strong I_Na and I_to blocker with some I_Ca blocking activity. The inhibition of I_to and other K⁺ efflux would prolong action potential duration, produce positive inotropic action and contribute to the negative chronotropic effect of (+)-MK801.

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Positive inotropic action of NMDA receptor antagonist (+)-MK801 in rat heart

Wang

1999

J Biomed Sci

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(+)-MK801, a noncompetitive NMDA receptor antagonist, was reported to exhibit anticonvulsive and neuroprotective activities during the postischemic period. Intravenous administration of (+)-MK801 produced tachycardia in rats, but bradycardia in pigs. We examined the mechanical and electrophysiological effects of (+)-MK801 on rat cardiac tissues. (+)-MK801 dose-dependently increased (3-100 microM) twitch tension in rat atria and ventricular strips. The spontaneous beating rate in rat right atria, however, was dose-dependently decreased by (+)-MK801. The inotropic effect of (+)-MK801 was affected neither by alpha(1)-antagonist (1 microM prazosin) nor by beta(1)-adrenoceptor antagonist (3 microM atenolol), but significantly by a transient outward K(+) channel blocker (3 mM 4-aminopyridine). (+)-MK801 did not cause any significant change of intracellular cAMP content. Electrophysiological study in rat ventricular cells revealed that (+)-MK801 concentration-dependently prolonged the action potential duration with a concomitant decrease in the maximum rate of the action potential upstroke (V(max)) and an increase in the recovery time constant of V(max). Voltage clamp study showed that (+)-MK801 (3 microM) reduced inward Na(+) current (I(Na)), along with a slowing of its recovery from inactivation and a slight negative shift of its voltage-dependent steady-state inactivation curves. At a much higher concentration (30 microM), (+)-MK801 slightly reduced the amplitude of L-type calcium inward current (I(Ca)), although the voltage dependence of its steady-state inactivation was unaffected. For the potassium currents in rat ventricular cells, 3 microM of (+)-MK801 reduced the peak transient outward current (I(to)), steady-state outward current (I(ss)) and inward current through K(1) channels. The inhibition of I(to) was associated with a prominent negative shift in the voltage dependence of its steady-state inactivation curve. The outward current through K(1) channels was unaffected. These results indicate that (+)-MK801 may be a strong I(Na) and I(to) blocker with some I(Ca) blocking activity. The inhibition of I(to) and other K(+) efflux would prolong action potential duration, produce positive inotropic action and contribute to the negative chronotropic effect of (+)-MK801.

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Mechanical and electrophysiological effects of a hydroxyphenyl-substituted tetrahydroisoquinoline, SL-1, on isolated rat cardiac tissues

Cited by 4 publications

References 22 publications

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA‐7, a furoquinoline alkaloid derivative, in rat heart

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA‐7, a furoquinoline alkaloid derivative, in rat heart

Positive Inotropic Action of NMDA Receptor Antagonist (+)-MK801 in Rat Heart

Positive inotropic action of NMDA receptor antagonist (+)-MK801 in rat heart

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Mechanical and electrophysiological effects of a hydroxyphenyl-substituted tetrahydroisoquinoline, SL-1, on isolated rat cardiac tissues

Cited by 4 publications

References 22 publications

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA‐7, a furoquinoline alkaloid derivative, in rat heart

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA‐7, a furoquinoline alkaloid derivative, in rat heart

Positive Inotropic Action of NMDA Receptor Antagonist (&plus;)-MK801 in Rat Heart

Positive inotropic action of NMDA receptor antagonist (+)-MK801 in rat heart

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Positive Inotropic Action of NMDA Receptor Antagonist (+)-MK801 in Rat Heart