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(Hypertension. 1999;34:514-519.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Pathophysiological Roles of Endothelin-1 in Dahl Salt-Sensitive Hypertension

Takanori Ikeda; Hisashi Ohta; Megumu Okada; Nobuko Kawai; Rumi Nakao; Peter K. S. Siegl; Tsutomu Kobayashi; Seiji Maeda; Takashi Miyauchi; Masaru Nishikibe

From the Department of Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical Co Ltd (T.I., H.O., M.O., N.K., R.N., T.K., M.N.); Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba (S.M., T.M.), Ibaraki, Japan; and Department of Cardiovascular Pharmacology, Merck Research Laboratories (P.K.S.S.), West Point, Penn.

Correspondence to Masaru Nishikibe, PhD, Department of Pharmacology, Development Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceutical Co Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan. E-mail niskbems{at}banyu.co.jp

Abstract—The purpose of the present experiment was to study the pathophysiological roles of endothelin-1 (ET-1) in salt-sensitive hypertension with the use of Dahl salt-sensitive (DS) and salt-resistant (DR) rats. PreproET-1 mRNA expression was determined by reverse transcription–polymerase chain reaction. In the kidney, expression of preproET-1 mRNA was greater in DS rats on a normal salt diet compared with DR rats of the same age. In DS rats, the level of preproET-1 mRNA expression in kidney had a significant correlation with systolic blood pressure. The expression of preproET-1 mRNA in aorta and kidney was increased by 3-week high salt intake in DS rats but not in DR rats. Expression of preproET-1 mRNA and ET-1 levels in left ventricle was exaggerated by high salt intake in DS rats. However, there was no significant difference in plasma ET-1 levels between DS and DR rats regardless of salt intake. Pressor response curves for ET-1 in DS rats with or without high salt intake were significantly shifted to the left compared with those in DR rats. A single oral dose (3 to 10 mg/kg) of J-104132 (L-753 037), a potent, orally active mixed endothelin A and B (ET_A/ET_B) receptor antagonist, reduced blood pressure to normotensive levels in DS rats with high salt intake, and its action was maintained for 24 hours. In DS rats with normal salt intake, J-104132 (10 mg/kg) slightly but significantly decreased blood pressure. DR rats did not show obvious depressor responses to J-104132 (10 mg/kg) regardless of salt intake. These results suggest that ET-1 acts as one of the pathophysiological factors in the development and maintenance of salt-sensitive hypertension, and a mixed ET_A/ET_B receptor antagonist could be useful in the treatment for salt-sensitive hypertension.

Key Words: endothelin • hypertension • rats, Dahl • kidney • receptors, endothelin

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