Extrarenal ET_B plays a significant role in controlling cardiovascular responses to high dietary sodium in rats

Endothelin-B receptor (ET_B)-deficient rats have low-renin, salt-sensitive hypertension. We hypothesized this was caused by an absence of renal ET_B signaling and performed a series of experiments to examine the effect of dietary sodium (Na) on endothelin-1 (ET1) expression and renal function in wild-type (WT) and ET_B-deficient rats. We found that ET_B deficiency, but not dietary Na, increases circulating and tissue (kidney and aorta) ET1 levels. Quantitative reverse-transcription polymerase chain reaction reveals that aortic and renal ET1 and endothelin-A receptor (ET_A) mRNA, however, are similarly increased by dietary Na in ET _B-WT and ET_B-deficient rats. We then determined the effect of chronic ET_A blockade on blood pressure (direct conscious measurements), urinary protein excretion, and creatinine clearance (Crcl). On a Na-deficient diet, ET_B-deficient rats have mild proteinuria and impaired Crcl. On a high-Na diet, severe hypertension and renal dysfunction develop in ET_B-deficient rats. Chronic ET_A blockade prevents hypertension and renal injury. To determine the role of the renal versus the extrarenal endothelin system, we performed renal cross- transplantation. We found that ET_B deficiency in the body is associated with renal injury and an impaired ability to excrete an Na load. We also found that ET_B deficiency in the body affects blood pressure response to dietary Na. Expression of ET1 and ET_A are regulated by dietary Na. ET_B receptors outside of the kidney, likely by functioning as a clearance receptor for ET1, limit salt-sensitivity in rats.