ELECTROPHYSIOLOGICAL EFFECTS OF S-16257, A NOVEL SINOATRIAL NODE MODULATOR, ON RABBIT AND GUINEA-PIG CARDIAC PREPARATIONS - COMPARISON WITH UL-FS-49
ELECTROPHYSIOLOGICAL EFFECTS OF S-16257, A NOVEL SINOATRIAL NODE MODULATOR, ON RABBIT AND GUINEA-PIG CARDIAC PREPARATIONS - COMPARISON WITH UL-FS-49
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DOI：
10.1111/j.1476-5381.1994.tb13025.x
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发表时间：
1994-05-01
影响因子：
7.3
通讯作者：
VILAINE, JP
中科院分区：
文献类型：
--
作者：
THOLLON, C;CAMBARRAT, C;VILAINE, JP
1 S 16257 是一种新型心动过缓剂。其电药理学特征与已知的心动过缓化合物 UL-FS 49（扎特布雷定）进行了比较。使用传统玻璃微电极进行细胞内动作电位 (AP) 记录。2 在兔离体窦房结 (SAN) 组织中，S 16257 和 UL-FS 49（1 μM、3 μM 和 10 μM）在减慢自发 AP 放电方面是等效的，主要通过降低舒张期去极化率（3 μM 时，- 23.8 +/- 3.9% 和 -分别为 27.9 +/- 2.6%）。对于这两种化合物，在 3 μM 时获得最大效果。在这些制剂中，在任何测试浓度下，总复极 (APD(50)) 50% 时的动作电位持续时间受 UL-FS 49 的影响比 S 16257 更大（3 μM 时，S 16257 和 UL-FS 49 分别为 + 8.9 +/- 2.9% 和 + 29.1 +/- 3.7%； P 小于或等于 0.01）。3 为了估计对 AP 持续时间的直接影响，将驱动心脏制剂暴露于这些药剂。在豚鼠乳头肌中，以 1 Hz 的频率起搏，增加 S 16257 或 UL-FS 49 的浓度（0.1 至 10 μM，每个浓度暴露 30 分钟）略微延长 AP 复极化。 UL-FS 49 的这种延长更为明显（对于 S 16257 和 UL-FS 49，APD(50) 分别在 1 μM 时 + 6.1 +/- 0.6% 和 + 11.2 +/- 1.3% 升高）。4 将 UL-FS 49 (3 μM) 应用于兔浦肯野纤维，以 0.25 Hz 的频率触发，诱导显着的延长APD(50) 和 APD(90)（分别为 + 149.4 +/- 51.2% 和 + 86.0 +/- 15.4%）。 S 16257 (3 μM) 仅诱导微弱的 AP 延长（APD(50) 和 APD(90) 分别为 + 14.1 +/- 5.0% 和 + 14.8 +/- 3.3%），显着小于 UL-FS 49.5 的情况。这些结果表明，S 16257 主要通过舒张压的降低，减慢了孤立 SAN 中自发 AP 放电的速率。细胞去极化，这表明起搏器电流（I-f）受到抑制。 S 16257 和 UL-FS 49 的心动过缓作用是等效的，但 S 16257 更具特异性，因为它引起心肌复极时间的增加较少。
1 S 16257 is a new bradycardic agent. Its electropharmacological profile has been compared to that of the known bradycardic compound UL-FS 49 (Zatebradine). Intracellular recordings of action potentials (APs) were performed with conventional glass microelectrodes.2 In the rabbit isolated sino-atrial node (SAN) tissue, S 16257 and UL-FS 49 (1 mu M, 3 mu M and 10 mu M) were equipotent in slowing spontaneous APs firing predominantly by decreasing the rate of diastolic depolarization (at 3 mu M, - 23.8 +/- 3.9% and - 27.9 +/- 2.6%, respectively). For the two compounds a maximal effect was obtained at 3 mu M. In these preparations, action potential duration at 50% of total repolarization (APD(50)) was more affected by UL-FS 49 than S 16257 at any concentration tested (at 3 mu M, + 8.9 +/- 2.9% and + 29.1 +/- 3.7% for S 16257 and UL-FS 49, respectively; P less than or equal to 0.01).3 To estimate the direct effects on AP duration, driven cardiac preparations were exposed to these agents. In guinea-pig papillary muscles, paced at a frequency of 1 Hz, increasing concentrations of S 16257 or UL-FS 49 (0.1 to 10 mu M, 30 min exposure for each concentration) slightly prolonged AP repolarization. This prolongation was more marked for UL-FS 49 (at 1 mu M, + 6.1 +/- 0.6% and + 11.2 +/- 1.3% elevation of APD(50), for S 16257 and UL-FS 49, respectively).4 Application of UL-FS 49 (3 mu M) to rabbit Purkinje fibres, triggered at a frequency of 0.25 Hz, induced a marked prolongation of APD(50) and APD(90) (+ 149.4 +/- 51.2% and + 86.0 +/- 15.4%, respectively). S 16257 (3 mu M) induced only a weak prolongation of AP (+ 14.1 +/- 5.0% and + 14.8 +/- 3.3% for APD(50) and APD(90), respectively) significantly smaller than in the case of UL-FS 49.5 These results show that S 16257 slows the rate of spontaneous AP firing in isolated SAN mainly by a reduction of the diastolic depolarization of the cells, which suggests an inhibition of the pace-maker current (I-f). S 16257 and UL-FS 49 are equipotent in their bradycardic effect but S 16257 is more specific as it induces less increase in myocardial repolarization time.