title: The role of endothelin in mediating ischemia/hypoxia-induced atrial natriuretic peptide release.
abstract: 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.
authors.affiliation: High Blood Pressure Research Unit, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: John R
authors.initials: JR
authors.lastname: Oliver
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000493:pharmacokinetics*; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D006321:Heart / Q000187:drug effects*; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D013449:Sulfonamides; D009320:Atrial Natriuretic Factor; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)