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Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA‐7, a furoquinoline alkaloid derivative, in rat heart
Author(s) -
Su MingJai,
Chang GwoJyh,
Wu MeiHwan,
Kuo ShengChu
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701510
Subject(s) - electrophysiology , alkaloid , chemistry , stimulation , membrane potential , antiarrhythmic agent , medicine , biophysics , steady state (chemistry) , repolarization , voltage clamp , inotrope , patch clamp , endocrinology , pharmacology , stereochemistry , biology , biochemistry , heart disease
1 HA‐7, a new synthetic derivative of furoquinoline alkaloid, increased the contractile force of right ventricular strips and effectively suppressed the ischaemia‐reperfusion induced polymorphic ventricular tachyrhythmias in adult rat heart (EC 50 =2.8 μ M ). 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 ( V̇ 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 m M 4‐AP. 3 Voltage clamp experiments revealed that HA‐7 decreased the maximal current amplitude of I Na (IC 50 =4.1 μ M ) 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 μ M , maximal inhibition=31.8%). 4 This agent also influenced 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 μ M ) and a slowly inactivating, steady‐state outward current (I ss ) (IC 50 =2.5 μ M ). 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 significant negative shift of the voltage‐dependent steady‐state inactivation curve but did not affect its rate of recovery from inactivation. 5 At higher concentrations, the inward rectifier K + current (I K1 ) was also inhibited but to a less extent. Its slope conductance after 3, 10 and 30 μ M 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 significant I to inhibition and minimal I Ca suppression may afford an opportunity to develop an effective antiarrhythmic agent linked with positive inotropy.