Abstract
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 hypothesized 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, 5 mg/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, 10 mg/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 ∼10 mmHg, 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.
Highlights
Hypertension is the single biggest contributor to global disease burden and remains a major risk factor for cardiovascular disease despite current multimodal therapeutic strategies [1, 2]
The major finding of our study was that administration of the ETA receptor antagonist, atrasentan, severely suppressed pressure natriuresis (PN) but reversed the salt-induced increase in systolic and diastolic Blood pressure (BP)
We considered that this might reflect a systemic vasodilatatory response to atrasentan that reduced the hemodynamic load on the kidneys since, overall, mean BP (MBP) and renal artery flow were decreased in the atrasentan group
Summary
Hypertension is the single biggest contributor to global disease burden and remains a major risk factor for cardiovascular disease despite current multimodal therapeutic strategies [1, 2]. The Guyton model has influenced hypertension research for more than 50 years but is challenged by an alternative hypothesis that salt-sensitivity is a manifestation of impaired vasodilatation rather than inadequate sodium and water excretion [6]. This is based on observations that dilatation of the systemic vasculature normally accommodates salt-induced intravascular volume expansion to buffer the effect on BP, while, in salt-sensitive individuals, vasodilatation is impaired and BP rises. The relative merits of these hypotheses are vigorously debated [6,7,8] but, in combination, they suggest that the ideal therapeutic agent for salt-sensitivity would be one that promotes dilatation, while at the same time promoting PN. Endothelin (ET) receptor antagonists offer considerable potential
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