Zhang, YiOliver, J MHorowitz, John D2015-12-132015-12-130160-2446http://hdl.handle.net/1885/76894The 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 × 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 reoxygenation. 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.Keywords: atrial natriuretic factor; bosentan; cyclo(dextro tryptophyl dextro aspartylprolyl dextro valylleucyl); endothelin; endothelin 1; endothelin receptor antagonist; oxygen; animal tissue; article; controlled study; heart atrium enlargement; heart muscle isch ANP; Endothelin; Endothelin receptor antagonists; Hypoxia; Ischemia; Isolated rat heart200410.1097/00005344-200402000-000102015-12-11