Hypertension is a major risk factor for cardiovascular disease. In a significant minority of people, it develops when salt intake is increased (salt-sensitivity). It is not clear whether this represents impaired vascular function or disruption to the relationship between blood pressure (BP) and renal salt-handling (pressure natriuresis, PN). Endothelin-1 (ET-1) regulates BP via ETA and ETB receptor subtypes. Blockade of ETA receptors reduces BP, but promotes sodium retention by an unknown mechanism. ETB blockade increases both BP and sodium retention. We hypothesised that ETA blockade promotes sodium and water retention by suppressing PN. We also investigated whether suppression of PN might reflect off-target ETB blockade. Acute PN was induced by sequential arterial ligation in male Sprague Dawley rats. Intravenous atrasentan (ETA antagonist, 5mg/kg) halved the normal increase in medullary perfusion and reduced sodium and water excretion by >60%. This was not due to off-target ETB blockade because intravenous A-192621 (ETB antagonist, 10mg/kg) increased natriuresis by 50% without modifying medullary perfusion. In a separate experiment in salt-loaded rats monitored by radiotelemetry, oral atrasentan reduced systolic and diastolic BP by ~10mmHg, but additional oral A-192621 reversed these effects. Endogenous ETA stimulation has natriuretic effects mediated by renal vascular dilation while endogenous ETB stimulation in the kidney has antinatriuretic effects via renal tubular mechanisms. Pharmacological manipulation of vascular function with ET antagonists modifies the BP set-point, but even highly selective ETA antagonists attenuate PN, which may be associated with salt and water retention.
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Research Article|
December 17 2021
The acute pressure natriuresis response is suppressed by selective ETA receptor blockade
Geoffrey Culshaw;
The University of Edinburgh The Queen's Medical Research Institute, Edinburgh, United Kingdom
* Corresponding Author; email: [email protected]
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David Binnie;
David Binnie
The University of Edinburgh The Queen's Medical Research Institute, Edinburgh, United Kingdom
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Neeraj Dhaun;
Neeraj Dhaun
The University of Edinburgh The Queen's Medical Research Institute, Edinburgh, United Kingdom
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Patrick Hadoke;
Patrick Hadoke
The University of Edinburgh The Queen's Medical Research Institute, Edinburgh, United Kingdom
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Matthew Bailey;
Matthew Bailey
The University of Edinburgh The Queen's Medical Research Institute, Edinburgh, United Kingdom
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David J Webb
David J Webb
The University of Edinburgh The Queen's Medical Research Institute, Edinburgh, United Kingdom
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Publisher: Portland Press Ltd
Received:
September 23 2021
Revision Received:
October 25 2021
Accepted:
December 16 2021
Online ISSN: 1470-8736
Print ISSN: 0143-5221
Copyright 2021 The Author(s)
2021
This is an Accepted Manuscript; not the final Version of Record. You are encouraged to use the final Version of Record that, when published, will replace this manuscript and be freely available under a Creative Commons licence.
Clin Sci (Lond) (2021) CS20210937.
Article history
Received:
September 23 2021
Revision Received:
October 25 2021
Accepted:
December 16 2021
Citation
Geoffrey Culshaw, David Binnie, Neeraj Dhaun, Patrick Hadoke, Matthew Bailey, David J Webb; The acute pressure natriuresis response is suppressed by selective ETA receptor blockade. Clin Sci (Lond) 2021; CS20210937. doi: https://doi.org/10.1042/CS20210937
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