Blood pressure-independent effect of angiotensin AT1 receptor blockade on renal endothelin-1 production in hypertensive uremic rats.
OBJECTIVE
We recently reported that treatment of uremic rats with reduced renal mass with the angiotensin II (Ang II) subtype 1 receptor (AT1) antagonist losartan reduces endothelin-1 (ET-1) levels in blood vessels and in glomeruli. Although this suggests an important role for Ang II in the modulation of ET-1 production, the concomitant decrease in blood pressure may also be involved. The present study was designed to investigate whether the modulation of ET-1 production in uremic rats is related to tissue-specific effects of AT1 receptor blockade or to the antihypertensive effect of losartan.


METHODS
One week after renal mass reduction, uremic rats were treated with the conventional triple therapy (TRx) [reserpine (5 mg/l), hydralazine (80 mg/l) and hydrochlorothiazide (25 mg/l)] or losartan (20 mg/kg per day) for 6 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma and urine, as well as in vascular and renal tissues were measured by a specific radioimmunoassay after sample extraction and purification.


RESULTS
Before treatment, systolic blood pressure was significantly higher in uremic animals compared to sham-operated controls (165+/-4 versus 123+/-2 mmHg, respectively; P < 0.01). Treatment with the TRx or with losartan normalized systolic blood pressure in uremic rats, whereas it was further increased in untreated uremic animals. At week 6, serum creatinine, proteinuria and urinary ET-1 and transforming growth factor-beta1 (TGF-beta1) excretion, as well as vascular and glomerular ET-1 content were increased in uremic rats compared to the controls (P < 0.01). Treatment of uremic rats with the TRx or with losartan reduced ET-1 content in the thoracic aorta and the mesenteric arterial bed (P < 0.01). However, losartan, but not the TRx, significantly attenuated the rise of serum creatinine, proteinuria and urinary ET-1 and TGF-beta1 excretion, as well as ET-1 content in glomeruli of uremic rats. Compared with the controls, renal preproET-1 mRNA expression was also significantly higher in uremic rats. Treatment of uremic rats with losartan prevented renal preproET-1 mRNA overexpression, indicating that changes in glomerular ET-1 content and urinary ET-1 excretion were related to modulation of renal ET-1 production.


CONCLUSIONS
These findings indicate that the effect of losartan on ET-1 production in peripheral blood vessels may be mediated, in part, by the reduction of blood pressure. In contrast, the reduction of renal ET-1 production is mediated by tissue-specific effects of AT1 receptor blockade, and may contribute to the renal protective effects of losartan.
Dumont
Y
Y
Research Center and Division of Nephrology, CHUQ, L'Hôtel-Dieu de Québec, Canada.
D'Amours
M
M
Lebel
M
M
Larivière
R
R
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000097:blood; D016232:Endothelins / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D013599:Systole; D014511:Uremia / Q000150:complications / Q000503:physiopathology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan