Endothelin-B Receptors Play an Important Role in Modulating Chronic Pressure-Natriuresis and Blood Pressure Regulation in Response to Changes in Dietary Sodium Intake.
Activation of the ETB receptor by endothelin (ET-1) has been shown to inhibit renal tubule transport, dilate renal microcirculatory vessels, and inhibit renin release. The purpose of this study was to determine the role of ET and ETB receptors in modulating renal-pressure natriuresis and blood pressure regulation in response to changes in dietary Na intake. To test whether the renal production of ET is enhanced in response to elevation in Na intake, the effects of a low (0.4%), normal (1.0%), or high (8%) Na diet on 24hr urinary excretion of ET-1 and mRNA expression of preproendothelin (ribonuclease protection assay) were determined. Increasing Na intake from low to normal levels had no effect on urinary ET-1 excretion or renal expression of preproendothelin. In contrast, increasing Na intake from normal to high levels resulted in significant increases in urinary excretion of ET-1 (7223±968 vs 2127±167 pg/24hrs) and expression of preproendothelin (42.3±6.7 vs 25.4±1.8 densitometric units) in the renal medulla. To test whether ETB receptors play an important role in modulating arterial pressure in response to changes in Na intake, the relationship between arterial pressure and sodium excretion was determined in control rats and in ETB receptor antagonist-treated rats (A-192621, 30mg/kg/day for 7 days). Long-term ETB receptor blockade resulted in a significant rightward shift in the chronic pressure-natriuresis relationship. In control rats on a normal and high Na intake, AP was 122±3 and 132±3mmHg, respectively. In contrast, AP in ETB receptor antagonist-treated rats on a normal and high Na intake was 144±2 and 171±12mmHg, respectively. In summary, we report that the renal endothelin system is upregulated in response to increases in sodium intake. Blockade of the ETB receptors results in significant hypertension that is salt-sensitive. These results indicate that endothelin via ETB receptors plays an important role in modulating renal-pressure natriuresis and blood pressure regulation in response to changes in dietary Na intake.