Evidence for metalloprotease involvement in the in vivo effects of big endothelin 1

Academic Article

Abstract

  • The potent vasoconstrictor endothelin 1 (ET-1) is thought to arise from the proteolytic processing of big endothelin 1 (Big ET) by a unique endothelin-converting enzyme, possibly a metalloprotease. Experiments were conducted to determine the effects of Big ET on cardiovascular and renal functions during inhibition of metalloprotease activity in vivo. Intravenous infusion of Big ET (0.1 nmol · kg-1 · min-1) in anesthetized euvolemic rats produced a significant increase in mean arterial pressure (MAP; 39 ± 8%) and a decrease in effective renal plasma flow (ERPF; -39 ± 2%), whereas glomerular filtration rate (GFR) remained unchanged (-8 ± 8%). Simultaneous intravenous infusion of phosphoramidon (0.25 mg · kg-1 · min-1), an inhibitor of metalloprotease activity including neutral endopeptidase EC 3.4.24.11 (NEP), completely prevented these effects of Big ET. Thiorphan (0.1 mg · kg-1 · min-1), also an inhibitor of NEP, had absolutely no effect on either the renal or cardiovascular response to Big ET. Similarly, the response to Big ET was unaffected by infusion of enalaprilat (0.1 mg · kg-1 · min-1), an inhibitor of the angiotensin-converting enzyme, which is also a metalloprotease. To determine whether the effect of phosphoramidon was due to antagonism of ET-1, an identical series of experiments was performed using ET-1 infusion (0.02 nmol · kg-1 · min-1). Although the increase in MAP (24 ± 5%) produced by ET-1 was less than that observed for the given dose of Big ET, the renal vasoconstriction was much more severe; the smaller peptide changed ERPF and GFR by -66 ± 7 and -54 ± 9%, respectively. None of the changes induced by ET-1 was affected by infusion of phosphoramidon, thiorphan, or enalaprilat. These results indicate that the hemodynamic effects of Big ET and ET-1 display different potencies in terms of the renal vs. systemic circulation. Furthermore, inhibition of the biological effects of Big ET by phosphoramidon is not via either direct or indirect antagonism of ET-1 thus supporting the idea that a unique, yet unidentified, metalloprotease is involved in producing the biological effects of Big ET, possibly by the specific conversion of Big ET to ET-1.
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    Author List

  • Pollock DM; Opgenorth TJ
  • Volume

  • 261
  • Issue

  • 1 30-1