Evidence for a direct vasoconstrictor effect of big endothelin-1 in the rat kidney.
Inhibition of endothelin-1 (ET-1)-converting enzyme has been suggested as a strategy for blocking ET-1-mediated vasoconstriction. However, it is unclear whether its putative substrate, bigET-1, is an inactive precursor. Thus, we compared in the rat the effects of ET-1 and bigET-1 on renal vascular resistance (RVR) in vitro (isolated perfused kidney, n = 15) and in vivo (Doppler shift technique, n = 23) when injected i.v. or in the rat renal artery (i.a.), before and after metalloprotease inhibition with phosphoramidon (30 mg/kg i.v.). In vitro, the ET-1/bigET-1 potency ratio for the RVR increase was 175; in vivo (i.v.) it was approximately 7 (ED50: 99 and 692 pmol/kg, respectively; P < 0.01). Unlike that of ET-1, the bigET-1 effect started slowly (peak effect at 15 min). On i.a. injection, the ED50 of ET-1 was lower but that of big ET-1 was unchanged (ED50: 28 and 706 pmol/kg, respectively). Moreover, the effect of i.a. bigET-1 on RVR was biphasic, with a dose-related rapid increase followed by a slowly developing further rise. Phosphoramidon completely inhibited the hemodynamic effects of i.v. bigET-1, but abolished only the second phase of the response when given i.a. It also significantly enhanced the effect of ET-1. We conclude that in the rat: (1) bigET-1 may affect RVR by both a direct effect and through phosphoramidon-sensitive conversion to ET-1; (2) the direct vasoconstrictor effect of bigET-1 might be expressed during endothelin-converting enzyme inhibition; (3) metalloproteases are involved in ET-1 degradation.
Salvati
P
P
Farmitalia Carlo Erba, Cardiovascular Department, Nerviano MI, Italy.
Dho
L
L
Calabresi
M
M
Rosa
B
B
Patrono
C
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016232:Endothelins; D006020:Glycopeptides; D014662:Vasoconstrictor Agents; C008890:phosphoramidon