title: Selective ET(A) receptor antagonism with ABT-627 attenuates all renal effects of endothelin in humans.
abstract: ++Endothelin (ET-1) acts as a potent vasoconstrictor in the human kidney, and this vasoconstriction could contribute to the ischemia seen in acute renal failure. In animal studies, the vasoactive properties of ET-1 are known to be ET(A) receptor-and/or ET(B) receptor-mediated; however, the receptor subtype involved in the human kidney remains to be defined. In a phase I, single-center, double-blind, randomized, three-period, crossover design, the effects of orally administered ABT-627, a selective ET(A) receptor antagonist, on renal hemodynamics during ET-1 infusion were evaluated. Two doses of ABT-627 (5 and 20 mg) were compared with placebo and nifedipine. For each dose level of ABT-627, a cohort of nine subjects was studied. A para-aminohippuric acid/inulin clearance test was performed once at the end of each 7-d treatment period. Infusion of ET-1 significantly decreased effective renal plasma flow, GFR, sodium excretion, and urine flow. Pretreatment with 20 mg of ABT-627 significantly decreased mean arterial pressure. In contrast, 7 d of treatment with both doses of ABT-627 did not affect baseline renal parameters. However, because mean arterial pressure decreased, a tendency toward a reduction of renal vascular resistance could indeed be demonstrated. Compared with placebo, both doses of ABT-627 were equally effective in blocking all renal effects caused by ET-1 infusion. In the model of exogenous ET-1 infusion, ABT-627 had a tendency to prevent ET-1-induced renal changes more effectively compared with nifedipine. The contribution of endogenous ET-1 and the ET(A) receptor in maintaining basal renal vascular tone in the human kidney is small. In addition, compared with placebo, selective ET(A) receptor antagonism with both doses of ABT-627 completely prevented all renal changes caused by ET-1 infusion.
authors.affiliation: Department of Vascular Medicine and Diabetes, University Hospital Utrecht, The Netherlands.|Clinical Pharmacology Unit, Utrecht, The Netherlands.
authors.forename: Marina L H
authors.initials: MLH
authors.lastname: Honing
authors.affiliation: Department of Vascular Medicine and Diabetes, University Hospital Utrecht, The Netherlands.|Clinical Pharmacology Unit, Utrecht, The Netherlands.
authors.forename: Michel L
authors.initials: ML
authors.lastname: Hijmering
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois.
authors.forename: David E
authors.initials: DE
authors.lastname: Ballard
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois.
authors.forename: Yonghong P
authors.initials: YP
authors.lastname: Yang
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Padley
authors.affiliation: Clinical Pharmacology Unit, Utrecht, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Morrison
authors.affiliation: Department of Vascular Medicine and Diabetes, University Hospital Utrecht, The Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
mesh_terms: D000328:Adult; D000077868:Atrasentan; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018592:Cross-Over Studies; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D012079:Renal Circulation / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D014662:Vasoconstrictor Agents; D009543:Nifedipine; D000077868:Atrasentan