Evidence for metalloprotease involvement in the in vivo effects of big endothelin 1.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Pollock
D M
DM
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064.
Opgenorth
T J
TJ
D000818:Animals; D004231:Diuresis / Q000187:drug effects; D015773:Enalaprilat / Q000494:pharmacology; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology / Q000502:physiology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006020:Glycopeptides / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009318:Natriuresis / Q000187:drug effects; D011188:Potassium / Q000652:urine; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D015244:Thiorphan / Q000494:pharmacology
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D015244:Thiorphan; D008666:Metalloendopeptidases; D015773:Enalaprilat; D011188:Potassium; C008890:phosphoramidon