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(Hypertension. 1998;31:995-1001.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Nephroprotection of an ET_A-Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

Stephan R. Orth; Jan P. Esslinger; Kerstin Amann; Ute Schwarz; Manfred Raschack; ; Eberhard Ritz

From the Departments of Internal Medicine and Pathology, Ruperto Carola University, Heidelberg, and Knoll AG, Ludwigshafen/Rhein, Germany.

Correspondence to Stephan R. Orth, MD, Medizinische Klinik, Bergheimer Str 56a, D-69115 Heidelberg, Germany.

Abstract—The present study was designed to assess whether the orally active and highly specific endothelin A (ET_A) receptor antagonist LU 135252 affects progressive renal dysfunction in a hypertensive rat model of renal damage, ie, the uninephrectomized (UNX) stroke-prone spontaneously hypertensive rat (SHRsp). The animals were examined on a normal salt (0.25%) diet and, to sensitize the kidney to hypertensive injury, also on a high salt (3%) diet. Stereological methods were used to quantify indices of glomerulosclerosis, vascular damage, and tubulointerstitial damage. Treatment with LU 135252 (100 mg/kg body wt) did not affect systolic blood pressure (BP) in animals on a normal salt diet during the whole period of the experiment (18 weeks) or in salt-loaded animals until week 10; subsequently, BP was slightly but significantly lower in salt-loaded UNX-SHRsp given LU 135252. Between weeks 6 and 12, 40% of the untreated UNX-SHRsp on a high salt diet, but none on a standard salt diet, died; such mortality was completely prevented by LU 135252. Indices of renal damage were more abnormal in salt-loaded UNX-SHRsp compared with UNX-SHRsp on a normal salt diet. Development of glomerulosclerosis and tubulointerstitial and vascular damage in UNX-SHRsp on high salt was completely prevented by LU 135252. The respective indices were no longer significantly different from those of salt-loaded sham-operated SHRsp controls. In the less severely damaged kidneys of UNX-SHRsp on normal salt, treatment with LU 135252 tended to ameliorate the indices, but the difference was not statistically significant. The results document a role of the ET system, specifically of ET_A receptors, in the development of progressive renal injury in salt-loaded UNX-SHRsp. LU 135252 completely prevented death and renal damage resulting from salt loading.

Key Words: endothelin • kidney • renal failure • receptors, endothelin • rats, inbred SHRsp

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