Endogenous endothelin generation maintains vascular tone in humans.
Endothelin-1 is a potent endothelium-derived vasoconstrictor and pressor peptide with uniquely sustained activity. We have examined the contribution of endogenously-generated endothelin-1 to the maintenance of basal vascular tone in healthy subjects. In these studies, on separate occasions, a combined inhibitor of endothelin converting enzyme (ECE) and neutral endopeptidase (NEP), phosphoramidon, a selective inhibitor of NEP, thiorphan, and a selective ETA receptor antagonist, BQ-123, were given via the brachial artery. Big endothelin-1, the precursor to endothelin-1, caused a slow onset dose-dependent forearm vasoconstriction, the magnitude of which was consistent with about 10% conversion to mature endothelin-1 in the forearm. Vasoconstriction to big endothelin-1 was abolished by co-infusion of phosphoramidon, whereas vasoconstriction to endothelin-1 was unaffected. Phosphoramidon caused progressive vasodilatation when infused alone, with blood flow increasing by 37% at 90 min (P = 0.02), whereas thiorphan caused vasoconstriction, consistent with NEP inhibition exerting its major effect on degradation of constrictor peptides, such as angiotensin and endothelin-1. Vasoconstriction to endothelin-1 was completely abolished by coinfusion of BQ-123, and BQ-123 alone produced progressive forearm vasodilatation, with blood flow increasing by 64% after 60 min (P = 0.001). These results demonstrate that endogenous production of endothelin-1 acts to sustain vascular tone in humans and indicate that ECE inhibitors and endothelium receptor antagonists may have therapeutic potential as vasodilators.
D000328:Adult; D001775:Blood Circulation / Q000187:drug effects; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology / Q000502:physiology*; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D008297:Male; D009129:Muscle Tonus / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D015244:Thiorphan / Q000494:pharmacology; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction; D014664:Vasodilation; D014666:Vasomotor System / Q000502:physiology*
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D011498:Protein Precursors; D015244:Thiorphan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon