The acute pressure natriuresis response is suppressed by selective ET(A) receptor blockade

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 ET(A) and ET(B) receptor subtypes. Blockade of ET(A) receptors reduces BP but promotes sodium retention by an unknown mechanism. ET(B) blockade increases both BP and sodium retention. We hypothesized that ET(A) blockade promotes sodium and water retention by suppressing PN. We also investigated whether suppression of PN might reflect off-target ET(B) blockade. Acute PN was induced by sequential arterial ligation in male Sprague Dawley rats. Intravenous atrasentan (ET(A) 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 ET(B) blockade because intravenous A-192621 (ET(B) 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 ET(A) stimulation has natriuretic effects mediated by renal vascular dilation while endogenous ET(B) 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 ET(A) antagonists attenuate PN, which may be associated with salt and water retention.