Endothelium-dependent modulation of responses to endothelin-I in human veins.
1. We have investigated whether local vascular production of nitric oxide or prostacyclin regulates venoconstriction induced by the endothelium-derived peptide, endothelin-1, in vivo in man. 2. Six healthy subjects received local dorsal hand vein infusion of endothelin-1 for 60 min alone or, on two separate occasions, co-infused with the donator of nitric oxide, glyceryl trinitrate, or the vasodilator prostaglandin, prostacyclin. In further studies, endothelin-1 was co-infused with an inhibitor of nitric oxide production, NG-monomethyl-L-arginine, or after oral administration of the irreversible inhibitor of prostaglandin production, acetylsalicylic acid (aspirin). 3. At a low dose (5 pmol/min), endothelin-1 alone caused slowly developing and long-lasting venoconstriction (maximal constriction: 66 +/- 4%). Although glyceryl trinitrate partially prevented endothelin-1-induced venoconstriction (maximum: 33 +/- 5%), inhibition of nitric oxide production did not affect endothelin-1-induced venoconstriction (maximum: 55 +/- 4%). 4. Prostacyclin was more effective at blocking the venoconstriction in response to endothelin-1 than glyceryl trinitrate (maximum: 12 +/- 3%), and there was substantial potentiation of endothelin-1-induced venoconstriction after pretreatment with aspirin (maximum: 90 +/- 3%). 5. Despite the capacity of nitric oxide to attenuate responses to endothelin-1, NG-monomethyl-L-arginine did not potentiate endothelin-1-induced venoconstriction, suggesting little or no stimulated production of nitric oxide in human veins. However, the potentiation of responses to endothelin-1 by aspirin indicates that endothelial production of prostacyclin attenuates responses to endothelin-1 in human veins in vivo.
Haynes
W G
WG
University of Edinburgh, Department of Medicine, Western General Hospital, U.K.
Webb
D J
DJ
D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D004357:Drug Synergism; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D019323:omega-N-Methylarginine
D016232:Endothelins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D011464:Epoprostenol; D005996:Nitroglycerin; D001241:Aspirin