The role of endothelin in mediating ischemia/hypoxia-induced atrial natriuretic peptide release

J Cardiovasc Pharmacol. 2004 Feb;43(2):227-33. doi: 10.1097/00005344-200402000-00010.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / pharmacology*
  • Atrial Natriuretic Factor / pharmacokinetics*
  • Bosentan
  • Endothelin Receptor Antagonists*
  • Endothelins / physiology*
  • Heart / drug effects*
  • Hypoxia / metabolism*
  • Male
  • Myocardial Ischemia / metabolism*
  • Peptides, Cyclic / pharmacology*
  • Radioimmunoassay
  • Rats
  • Sulfonamides / pharmacology*

Substances

  • Antihypertensive Agents
  • Endothelin Receptor Antagonists
  • Endothelins
  • Peptides, Cyclic
  • Sulfonamides
  • Atrial Natriuretic Factor
  • Bosentan
  • cyclo(Trp-Asp-Pro-Val-Leu)