Pankucsi C, Bányász T, Magyar J, Gyönös I, Kovács A, Varró A, Szénási G, Nánási P P
Department of Physiology, University Medical School of Debrecen, Hungary.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Mar;355(3):398-405. doi: 10.1007/pl00004960.
The cellular electrophysiological effects of EGIS-7229 (5-chlor-4-[N-(3,4-dimethoxy-phenyl-ethyl)-amino-propylamino]-3 (2H)-pyridazinone fumarate), a novel antiarrhythmic agent, was studied using conventional microelectrode techniques in canine cardiac Purkinje fibers and papillary muscle preparations obtained from man, rabbits and guinea pigs. Low concentration of EGIS-7229 (3 mumol/l) selectively lengthened action potential duration (both APD50 and APD90) in all preparations. The effect of higher concentrations (30-100 mumol/l) of EGIS-7229 on action potential duration was variable depending on the preparation studied: in rabbit and human papillary muscles both APD50 and APD90 were lengthened, in canine Purkinje fibers APD90 was lengthened but APD50 was shortened, while in guinea pig papillary muscles both APD50 and APD90 were shortened by high concentrations of the drug. At these higher concentrations EGIS-7229 also decreased the maximum velocity of action potential upstroke (Vmax) and depressed the plateau of action potentials without affecting the resting membrane potential or action potential amplitude. Both reduction of Vmax and lengthening of APD were frequency dependent. The former effect was more prominent at higher pacing frequencies, while the latter was more pronounced at lower driving rates. In guinea pig papillary muscle, the time constant of recovery from Vmax-block was 719 +/- 33 ms (n = 18) and the rate of onset of the block was 1.81 +/- 0.06 AP-1 (n = 16) in the presence of 100 mumol/l EGIS-7229. EGIS-7229 had a complex action on refractoriness in guinea pig papillary muscles: ERP was lengthened at low concentrations (3 to 10 mumol/l), unchanged at 30 mumol/l and shortened at 100 mumol/l. The ratio of ERP/APD90, however, was significantly increased at concentrations higher than 3 mumol/l. In canine Purkinje fiber, when the delayed rectifier K current (IK) was blocked by d-sotalol (60 mumol/l) and APD was shortened back to its control value by additional application of nicorandil (15 mumol/l), APD was not affected by 3 mumol/l but was shortened by 30 mumol/l of EGIS-7229. 100 mumol/l EGIS-7229 shortened APD in guinea pig papillary muscle. This effect of EGIS-7229 was effectively prevented by nifedipine pretreatment (10 mumol/ l). In this preparation, EGIS-7229 also decreased the Vmax of the slow action potential, evoked in the presence of 20 mmol/l external K+ plus 0.5 mmol/l Ba2+. It is likely that EGIS-7229 at low concentrations blocks IK in human, canine, rabbit and guinea pig cardiac preparations, but at higher concentrations also inhibits Ca and Na currents. Therefore, EGIS-7229 appears to carry mixed class III, IV and IB antiarrhythmic properties.
采用传统微电极技术，在犬心脏浦肯野纤维以及从人、兔和豚鼠获取的乳头肌标本中，研究了新型抗心律失常药物EGIS - 7229（5 - 氯 - 4 - [N - (3,4 - 二甲氧基 - 苯乙基) - 氨基丙基氨基] - 3(2H) - 哒嗪酮富马酸盐）的细胞电生理效应。低浓度的EGIS - 7229（3 μmol/l）可选择性延长所有标本中的动作电位时程（APD50和APD90）。较高浓度（30 - 100 μmol/l）的EGIS - 7229对动作电位时程的影响因所研究的标本而异：在兔和人乳头肌中，APD50和APD90均延长；在犬浦肯野纤维中，APD90延长但APD50缩短；而在豚鼠乳头肌中，高浓度药物使APD50和APD90均缩短。在这些较高浓度下，EGIS - 7229还降低动作电位上升的最大速度（Vmax）并压低动作电位的平台期，而不影响静息膜电位或动作电位幅度。Vmax的降低和APD的延长均呈频率依赖性。前一种效应在较高起搏频率时更显著，而后一种效应在较低驱动频率时更明显。在豚鼠乳头肌中，在100 μmol/l EGIS - 7229存在时，从Vmax阻断恢复的时间常数为719±33 ms（n = 18），阻断的起始速率为1.81±0.06 AP-1（n = 16）。EGIS - 7229对豚鼠乳头肌的不应期有复杂作用：低浓度（3至10 μmol/l）时ERP延长，30 μmol/l时不变，100 μmol/l时缩短。然而，在高于3 μmol/l的浓度下，ERP/APD90的比值显著增加。在犬浦肯野纤维中，当延迟整流钾电流（IK）被d - 索他洛尔（60 μmol/l）阻断且通过额外应用尼可地尔（15 μmol/l）使APD缩短回到其对照值时，3 μmol/l的EGIS - 7229对APD无影响，但30 μmol/l的EGIS - 7229使其缩短。100 μmol/l的EGIS - 7229使豚鼠乳头肌的APD缩短。硝苯地平预处理（10 μmol/l）可有效防止EGIS - 7229的这种效应。在该标本中，EGIS - 7229还降低了在20 mmol/l细胞外K⁺加0.5 mmol/l Ba²⁺存在时诱发的慢动作电位的Vmax。低浓度的EGIS - 7229可能在人、犬、兔和豚鼠心脏标本中阻断IK，但在较高浓度时也抑制钙电流和钠电流。因此，EGIS - 7229似乎具有Ⅲ类、Ⅳ类和ⅠB类抗心律失常的混合特性。
