Department of Cell Physiology, Akita University Graduate School of Medicine, Japan.
J Pharmacol Sci. 2012;118(2):255-65. doi: 10.1254/jphs.11202fp. Epub 2012 Feb 1.
The ultra-short acting, selective β(1)-adrenergic antagonists landiolol and esmolol are widely used perioperatively; however, little is known about their acute direct actions on the heart. The current study utilized the Langendorff perfused heart system to measure changes in cardiac function and hemodynamics in response to each drug. Furthermore, electrophysiological analysis was performed on isolated ventricular myocytes. Direct application of esmolol significantly decreased systolic left ventricular pressure and heart rate at concentrations > 10 µM, while it dose-dependently increased coronary perfusion pressure. Esmolol also shortened the action potential duration (APD) in a concentration-dependent manner, an action maintained even when the delayed rectifier K(+) current or ATP sensitive K(+) current was blocked. Moreover, esmolol inhibited both the inward rectifier K(+) current (I(K1)) and the L-type Ca(2+) current (I(CaL)) and increased the outward current dose-dependently. In contrast, landiolol had minimal cardiac effects. In the Kyoto Model computer simulation, inhibition of either I(K1) or I(CaL) alone failed to shorten the APD; however, an additional increase in the time-independent outward current caused shortening of the APD, equal to that induced by esmolol. In conclusion, esmolol directly inhibits cardiac performance significantly more so than landiolol, an effect revealed to be at least in part mediated by esmolol-induced APD shortening.
超短效、选择性β(1)-肾上腺素能拮抗剂拉贝洛尔和艾司洛尔在围手术期广泛应用；然而，关于其对心脏的急性直接作用知之甚少。本研究利用 Langendorff 灌流心脏系统测量了心脏功能和血流动力学对每种药物的变化。此外，还对分离的心室肌细胞进行了电生理分析。艾司洛尔的直接应用显著降低了收缩压左心室压和心搏率在浓度>10 µM，而它浓度依赖性地增加冠状动脉灌注压。艾司洛尔还缩短了动作电位时程（APD），这种作用在阻断延迟整流钾电流（I(K+)）或ATP 敏感钾电流（I(KATP)）时仍然存在。此外，艾司洛尔抑制内向整流钾电流（I(K1)）和 L 型钙电流（I(CaL)），并呈浓度依赖性增加外向电流。相比之下，拉贝洛尔对心脏的影响很小。在京都模型计算机模拟中，单独抑制 I(K1)或 I(CaL)均不能缩短 APD；然而，非时相外向电流的增加导致 APD 缩短，与艾司洛尔诱导的 APD 缩短相当。总之，艾司洛尔对心脏功能的直接抑制作用明显大于拉贝洛尔，这种作用至少部分是由艾司洛尔诱导的 APD 缩短介导的。
