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(Hypertension. 2005;45:940.)
© 2005 American Heart Association, Inc.

Original Articles

Extrarenal ET_B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

Mamoru Ohkita; Yuqin Wang; Ngoc Diep T. Nguyen; Yu-Hwai Tsai; S. Clay Williams; Richard C. Wiseman; Paul D. Killen; Shujun Li; Masashi Yanagisawa; Cheryl E. Gariepy

From the Departments of Pediatrics (M.O., N.D.T.N., Y.-H.T., C.E.G.) and Pathology (P.D.K.), University of Michigan, Ann Arbor; Howard Hughes Medical Institute (M.Y.) and Departments of Pathology (S.C.W.), Transplant Surgery (Y.W., S.L.), and Molecular Genetics (R.C.W., M.Y.), The Donald W. Reynolds Cardiovascular Clinical Research Center (M.Y.), University of Texas Southwestern Medical Center, Dallas, Tex.

Correspondence to Masashi Yanagisawa, MD, PhD, Howard Hughes Medical Institute, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Y5-224, Dallas, TX 75235-9050. E-mail Masashi.Yanagisawa{at}UTSouthwestern.edu or Cheryl E. Gariepy, MD, Department of Pediatrics and Communicable Diseases, University of Michigan, Medical Science Research Building I, A520, Ann Arbor, MI 48109-0656. E-mail CGariepy@med.umich.edu

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.

Key Words: endothelin • natriuresis • proteinuria • sympathetic nervous system • transplantation

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