title: Role of endothelin receptor subtypes in the systemic and renal responses to endothelin-1 in humans.
abstract: The authors recently reported that infusion of endothelin-1 in humans to obtain pathophysiological plasma levels causes profound renal vasoconstriction and sodium retention. The relative roles of the ETA- and ETB-receptor subtypes in these effects in humans is unknown. Such information is essential in view of the recent introduction of endothelin-receptor blockers in clinical medicine. The study presented here was designed to define the role of the ETA- and ETB-receptor subtypes in the renal actions of endothelin-1 in humans. Systemic infusion of endothelin-1, a nonselective receptor agonist, was compared with infusion of equimolar dosages of the ETB-selective agonist endothelin-3 in healthy volunteers. Endothelin-1 infusion was associated with an approximate 2.5-fold increase in plasma levels of endothelin-1. This was accompanied by an increase in blood pressure by approximately 6 mm Hg (P < 0.05). During endothelin-1 infusion, RPF decreased from 642 +/- 42 to 480 +/- 36 mL/min (P < 0.05) and GFR from 121 +/- 4 to 109 +/- 7 mL/min (P < 0.05). Sodium excretion rate decreased during endothelin-1 infusion, from a baseline value of 182 +/- 33 to 84 +/- 28 mumol/min at the end of the endothelin-1 infusion. Endothelin-3 infusion also resulted in a approximate 2.5-fold increase of plasma levels of endothelin-3. However, in contrast to the endothelin-1 infusion, endothelin-3 had no effect on blood pressure, renal hemodynamics, and electrolyte excretion. These results suggest that the systemic and renal vasoconstrictor effects of endothelin-1 in humans are predominantly mediated by the ETA receptors.
authors.affiliation: Department of Nephrology and Hypertension, University Hospital Utrecht, The Netherlands.
authors.forename: K A
authors.initials: KA
authors.lastname: Kaasjager
authors.forename: S
authors.initials: S
authors.lastname: Shaw
authors.forename: H A
authors.initials: HA
authors.lastname: Koomans
authors.forename: T J
authors.initials: TJ
authors.lastname: Rabelink
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D019334:Endothelin-3 / Q000008:administration & dosage / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D008094:Lithium / Q000652:urine; D008297:Male; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D019334:Endothelin-3; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D000450:Aldosterone; D008094:Lithium; D012964:Sodium; D012083:Renin