Pugsley M K, Saint D A, Hayes E, Berlin K D, Walker M J
Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada. RSDAA/unixg.ubc.ca
Eur J Pharmacol. 1995 Dec 27;294(1):319-27. doi: 10.1016/0014-2999(95)00551-x.
This study compares the cardiovascular and antiarrhythmic effects of sparteine and a 3,7-diheterobicyclo[3.3.1]nonane analogue of sparteine, BRB-I-28, in pentobarbitone-anaesthetized rats subjected to left-ventricle electrical stimulation and occlusion of the left anterior descending coronary artery. Sparteine and BRB-I-28 produced a dose-dependent reduction in heart rate and blood pressure over the dose range 1-64 mumol/kg/min. As well, the P-R and Q-aT intervals of the electrocardiogram (ECG) were prolonged. The thresholds for induction of premature beats and ventricular fibrillation were dose-dependently increased and both drugs increased refractoriness. While sparteine and BRB-I-28 (at 16 and 64 mumol/kg/min, respectively) did not change the incidence of premature beats or ventricular tachycardia with coronary occlusion, both drugs equally reduced the incidence of ventricular fibrillation. We characterized the actions of sparteine and BRB-I-28 on cardiac Na+, transient outward and sustained outward plateau K+ currents of rat myocytes using the whole-cell patch-clamp. Sparteine and BRB-I-28 produced a concentration-dependent reduction in Na+ current with EC50 values of 110 and 230 microM, respectively. Both drugs produced hyperpolarizing shifts of 8 and 11 mV, respectively, for Na+ channel inactivation while neither produced a change in channel activation. Both drugs produced a concentration-dependent block of the sustained plateau K+ current and increased the rate of decay of the transient outward K+ current. Thus, sparteine and BRB-I-28 possess Na+ and K+ channel blocking properties which may account for their antiarrhythmic actions against electrical and ischaemic arrhythmias.
本研究比较了鹰爪豆碱及其3,7 - 二杂双环[3.3.1]壬烷类似物BRB - I - 28，在戊巴比妥麻醉的大鼠中，对左心室进行电刺激以及结扎左冠状动脉前降支时的心血管和抗心律失常作用。在1 - 64 μmol/kg/min的剂量范围内，鹰爪豆碱和BRB - I - 28可使心率和血压呈剂量依赖性降低。此外，心电图（ECG）的P - R和Q - aT间期延长。诱发早搏和心室颤动的阈值呈剂量依赖性增加，且两种药物均增加了不应期。虽然鹰爪豆碱和BRB - I - 28（分别为16和64 μmol/kg/min）在冠状动脉闭塞时未改变早搏或室性心动过速的发生率，但两种药物均同等程度地降低了心室颤动的发生率。我们使用全细胞膜片钳技术，研究了鹰爪豆碱和BRB - I - 28对大鼠心肌细胞的心脏钠电流、瞬时外向电流和持续外向平台钾电流的作用。鹰爪豆碱和BRB - I - 28分别使钠电流呈浓度依赖性降低，其半数有效浓度（EC50）值分别为110和230 μM。两种药物分别使钠通道失活发生8和11 mV的超极化偏移，而对通道激活均无影响。两种药物均使持续平台钾电流呈浓度依赖性阻滞，并增加了瞬时外向钾电流的衰减速率。因此，鹰爪豆碱和BRB - I - 28具有钠通道和钾通道阻滞特性，这可能解释了它们对电和缺血性心律失常的抗心律失常作用。
