First-in-Man Demonstration of Direct Endothelin-Mediated Natriuresis and Diuresis

Robert W. Hunter, Rebecca Moorhouse, Tariq E. Farrah, Iain M. MacIntyre, Takae Asai, Peter J. Gallacher, Debbie Kerr, Vanessa Melville, Alicja Czopek, Emma E. Morrison, Jess R. Ivy, James W. Dear, Matthew A. Bailey, Jane Goddard, David J. Webb, Neeraj Dhaun

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Endothelin (ET) receptor antagonists are potentially novel therapeutic agents in chronic kidney disease and resistant hypertension, but their use is complicated by sodium and water retention. In animal studies, this side effect arises from ETB receptor blockade in the renal tubule. Previous attempts to determine whether this mechanism operates in humans have been confounded by the hemodynamic consequences of ET receptor stimulation/blockade. We aimed to determine the effects of ET signaling on salt transport in the human nephron by administering subpressor doses of the ET-1 precursor, big ET-1. We conducted a 2-phase randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. After sodium restriction, subjects received either intravenous placebo or big ET-1, in escalating dose (≤300 pmol/min). This increased plasma concentration and urinary excretion of ET-1. Big ET-1 reduced heart rate (≈8 beats/min) but did not otherwise affect systemic hemodynamics or glomerular filtration rate. Big ET-1 increased the fractional excretion of sodium (from 0.5 to 1.0%). It also increased free water clearance and tended to increase the abundance of the sodium-potassium-chloride cotransporter (NKCC2) in urinary extracellular vesicles. Our protocol induced modest increases in circulating and urinary ET-1. Sodium and water excretion increased in the absence of significant hemodynamic perturbation, supporting a direct action of ET-1 on the renal tubule. Our data also suggest that sodium reabsorption is stimulated by ET-1 in the thick ascending limb and suppressed in the distal renal tubule. Fluid retention associated with ET receptor antagonist therapy may be circumvented by coprescribing potassium-sparing diuretics.

Original languageEnglish
Early online date15 May 2017
Publication statusPublished - 1 Jul 2017

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  • Journal Article


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