Phosphoramidon inhibits the vasoconstrictor effects evoked by big endothelin-1 but not the elevation of plasma endothelin-1 in vivo.
Intravenous injections of big endothelin (ET)-1 (700 pmol/kg) in the pig increased arterial plasma levels of ET-1-like immunoreactivity (ET-1-LI) from 11.1 +/- 0.7 pM to 46.3 +/- 6.7 pM in the control situation and from 11.5 +/- 0.4 pM to 58.2 +/- 17 pM in the presence of the neutral endopeptidase inhibitor phosphoramidon (3 mg/kg). Big ET-1 increased splenic vascular resistance by 29% in the control situation. The vasoconstriction evoked by big ET-1 in the spleen was reduced after phosphoramidon treatment whereas the elevation of arterial ET-1-LI was not influenced. Furthermore the splenic vasoconstriction evoked by ET-1 was reduced after phosphoramidon without influencing plasma ET-1-LI. Also in rats the pressor effect of big ET-1 (1 nmol/kg) was inhibited by phosphoramidon (5 mg/kg) whereas the elevation of plasma ET-1 was not influenced. It is concluded that the vasoconstrictor effects of both big ET-1 and ET-1 are inhibited, but the increase in plasma ET-1 is unaffected by phosphoramidon.
Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
A
A
Modin
J
J
Pernow
J M
JM
Lundberg
D000818:Animals; D019332:Endothelin-1; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000097:blood*; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011498:Protein Precursors / Q000037:antagonists & inhibitors*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000098:blood supply; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D015260:Neprilysin; C008890:phosphoramidon