Nephroprotection of an ET(A)-receptor blocker (LU 135252) in salt-loaded uninephrectomized stroke-prone spontaneously hypertensive rats.
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.
Orth
S R
SR
Department of Internal Medicine, Ruperto Carola University, Heidelberg, Germany.
Esslinger
J P
JP
Amann
K
K
Schwarz
U
U
Raschack
M
M
Ritz
E
E
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000209:etiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D007668:Kidney / Q000033:anatomy & histology / Q000187:drug effects*; D008297:Male; D009392:Nephrectomy / Q000009:adverse effects; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D044022:Receptor, Endothelin A; D012982:Sodium, Dietary / Q000009:adverse effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D012982:Sodium, Dietary; C107831:darusentan