Sharif I, Crockett T R, Kane K A, Wainwright C L
Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, 27 Taylor Street, Glasgow G4 0NR, Scotland, UK.
Eur J Pharmacol. 2001 Sep 21;427(3):235-42. doi: 10.1016/s0014-2999(01)01248-1.
We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1-10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K+) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K+ (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21-30-min post-occlusion period. Furthermore, in hearts perfused with low K+ solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.
我们之前已经表明，在冠状动脉闭塞前静脉注射小剂量的内皮素-1，对麻醉大鼠具有显著的抗心律失常作用。本研究的目的是通过评估内皮素-1对大鼠离体心脏闭塞诱导的心律失常的抗心律失常作用，来确定这是否是由于内皮素-1对心脏的直接作用。大鼠离体心脏采用Langendorff模式（恒流）灌注，并进行冠状动脉闭塞30分钟。在整个实验过程中监测冠状动脉灌注压和体表心电图（ECG）。在第一系列研究中，评估了在冠状动脉闭塞前三次输注5分钟内皮素-1（0.1 - 10 nM）的效果。第二组心脏在缺血前5分钟给予单次推注剂量的内皮素-1（10 pmol）。第三系列实验使用改良的（低钾）Krebs Henseleit溶液来增加缺血诱导的心室颤动（VF）的发生率。在这些心脏中，内皮素-1（0.1或2 pmol）在缺血前5分钟作为推注给药。缺血前输注内皮素-1在任何使用的浓度下均未改变心律失常的发生率或严重程度。在灌注含正常钾（4.4 mM）的Kreb's Henseleit溶液的心脏中，推注内皮素-1（10 pmol）被发现会导致冠状动脉灌注压略有升高，且无先前的降压反应。在这些条件下，内皮素-1仅通过减少闭塞后21 - 30分钟期间的心律失常计数，对心律失常产生非常适度的降低作用。此外，在灌注低钾溶液的心脏中，推注内皮素-1，剂量要么对冠状动脉灌注压无影响（0.1 pmol），要么产生显著的血管舒张作用且无显著的升压作用（2 pmol），对心室颤动均无影响。因此，在足以对冠状动脉血管产生作用的浓度下，内皮素-1在离体心脏制剂中未能改变心律失常。这些结果表明，先前在体内观察到的内皮素-1的抗心律失常作用并非由于对心肌或冠状动脉血管的直接作用。
