Contribution of endogenous generation of endothelin-1 to basal vascular tone.
Endothelin-1 is an endothelium-derived vasoconstrictor peptide, possibly involved in the pathophysiology of cardiovascular disease. We examined the contribution of endogenously generated endothelin-1 to maintenance of peripheral vascular tone in healthy subjects by local intraarterial administration of an inhibitor of endothelin converting enzyme, phosphoramidon, and of a selective endothelin receptor A antagonist, BQ-123. Brachial artery infusion of local doses of proendothelin-1, the precursor to endothelin-1, caused a slow-onset dose-dependent forearm vasoconstriction which was abolished by co-infusion of phosphoramidon. Phosphoramidon did not affect responses to endothelin-1. Phosphoramidon caused slow-onset vasodilatation when infused alone, with blood flow increasing by 37% at 90 min (p = 0.03). Vasoconstriction to endothelin-1 was abolished by co-infusion of BQ-123 (p = 0.006), with forearm blood flow tending to increase. Infusion of BQ-123 alone caused progressive vasodilatation, with blood flow increasing by 64% after 60 min (p = 0.007). These results show that endogenous production of endothelin-1 contributes to the maintenance of vascular tone. Endothelin converting enzyme inhibitors and receptor antagonists may have therapeutic potential as vasodilators.
Haynes
W G
WG
University of Edinburgh, Department of Medicine, Western General Hospital, UK.
Webb
D J
DJ
D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D005542:Forearm / Q000098:blood supply*; D006020:Glycopeptides / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010456:Peptides, Cyclic / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
D000900:Anti-Bacterial Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D010456:Peptides, Cyclic; D011498:Protein Precursors; C093240:proendothelin 1; D015260:Neprilysin; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon