Zhang Yi, Oliver John R, Horowitz John D
High Blood Pressure Research Unit, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
J Cardiovasc Pharmacol. 2004 Feb;43(2):227-33. doi: 10.1097/00005344-200402000-00010.
The aim of the present study was to investigate the putative role of endothelin (ET) in mediating ischemia/hypoxia-induced ANP release utilizing exogenous ET-1 or ET receptor antagonists (BQ-123 or Bosentan). Isolated rat hearts with non-distended atria were perfused using a Langendorff apparatus and heart rate maintained constant via atrial pacing. Global ischemia was induced either by direct reduction in perfusion or by infusion of exogenous ET-1 (5 x 10(-10) M) for 30 minutes. Perfusion with the ET receptor antagonists, BQ-123 (10(-6) M) or Bosentan (10(-5) M) was initiated 10 minutes before onset of ischemia. Moderate or severe ischemia was induced by reduction (52-61% and 70-82%, respectively) in perfusate flow. Thirty minutes of ischemia/hypoxia (5% O2) was followed by 30 minutes of reperfusion/re-oxygenation. Both moderate and severe ischemia increased ANP release. BQ-123 and Bosentan did not affect basal or ischemia-induced ANP release. Exogenous ET-1 perfusion induced a late increase in ANP release (P < 0.01) that did not exceed the increase in ANP release associated with equivalent direct flow reduction. Hypoxia induced an 8-fold increase in ANP release rate. The ANP release rate returned toward basal levels after re-oxygenation. Bosentan, but not BQ-123, significantly attenuated (P < 0.01) hypoxia-induced ANP release. In conclusion, in this system, ANP release is stimulated by moderate (or severe) ischemia and severe hypoxia independent of change in atrial distension; endogenous ET does not mediate basal and ischemia-induced ANP release; and hypoxia-induced ANP release is partially modulated via interaction with endogenous ET.
本研究的目的是利用外源性内皮素-1（ET-1）或内皮素受体拮抗剂（BQ-123或波生坦）来研究内皮素（ET）在介导缺血/缺氧诱导的心房钠尿肽（ANP）释放中的假定作用。使用Langendorff装置灌注分离的大鼠心脏，其心房未扩张，并通过心房起搏使心率保持恒定。通过直接降低灌注或输注外源性ET-1（5×10⁻¹⁰ M）30分钟来诱导整体缺血。在缺血开始前10分钟开始用ET受体拮抗剂BQ-123（10⁻⁶ M）或波生坦（10⁻⁵ M）进行灌注。通过降低灌注液流量（分别为52 - 61%和70 - 82%）诱导中度或重度缺血。30分钟的缺血/缺氧（5% O₂）后接着进行30分钟的再灌注/再氧合。中度和重度缺血均增加了ANP的释放。BQ-123和波生坦不影响基础或缺血诱导的ANP释放。外源性ET-1灌注诱导ANP释放的后期增加（P < 0.01），但不超过与同等直接流量降低相关的ANP释放增加。缺氧使ANP释放速率增加8倍。再氧合后ANP释放速率恢复至基础水平。波生坦而非BQ-123显著减弱（P < 0.01）缺氧诱导的ANP释放。总之，在该系统中，中度（或重度）缺血和重度缺氧刺激ANP释放，与心房扩张变化无关；内源性ET不介导基础和缺血诱导的ANP释放；缺氧诱导的ANP释放通过与内源性ET相互作用而部分受到调节。
