Venoconstriction to endothelin-1 in humans is attenuated by local generation of prostacyclin but not nitric oxide.

Abstract

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.