Venoconstriction to endothelin-1 in humans is attenuated by local generation of prostacyclin but not nitric oxide.
Endothelin-1 (ET-1) is known to be a potent and long-lasting constrictor of arteries and veins. We investigated whether local endothelial production of nitric oxide (NO) or prostacyclin modulates venoconstriction induced by the endothelium-derived peptide ET-1 in vivo in humans. Six healthy volunteers each received local dorsal hand vein infusion of ET-1 (5 pmol/min) for 60 min in five separate studies: once given alone; on three occasions co-infused with either the NO donor glyceryl trinitrate (GTN), the vasodilator prostaglandin, prostacyclin, or the inhibitor of nitric oxide synthase (NOS) NG-monomethyl-arginine (L-NMMA); and once given 30 min after oral administration of the irreversible inhibitor of cyclooxygenase, acetylsalicylic acid (aspirin). ET-1 alone caused slowly developing and long-lasting venoconstriction (maximal constriction 66 +/- 4%). Although GTN partially prevented ET-1-induced constriction (maximum 33 +/- 5%, p = 0.004 versus ET-1), inhibition of NOS did not affect ET-1-induced venoconstriction (maximum 55 +/- 4%). Prostacyclin was more effective at blocking the venoconstriction to ET-1 than GTN (maximum 12 +/- 3%, p = 0.0001) and there was substantial potentiation of ET-1-induced venoconstriction after pretreatment with aspirin (maximum 90 +/- 3%, p = 0.001). Despite the capacity of NO to attenuate responses to ET-1, L-NMMA did not potentiate ET-1-induced venoconstriction, suggesting little or no stimulated production of NO by ET-1 in human hand veins. However, substantial potentiation of ET-1-induced venoconstriction by aspirin indicates that endothelial production of prostacyclin modulates responses to ET-1 in human veins in vivo.
Webb
D J
DJ
University of Edinburgh, Department of Medicine, Western General Hospital, Scotland.
Haynes
W G
WG
D000328:Adult; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis*; D006225:Hand / Q000098:blood supply; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D019323:omega-N-Methylarginine
D016232:Endothelins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D005996:Nitroglycerin; D001241:Aspirin