Antihypertensive and renal protective effects of renin-angiotensin system blockade in uremic rats treated with erythropoietin.
BACKGROUND
Correcting anemia with recombinant human erythropoietin (rhEPO) in chronic renal failure has been associated with an increased blood pressure (BP), which may accelerate the decline in renal function. This has been attributed, in part, to the activation of the renin-angiotensin system. The present study was designed to investigate the protective effect of the angiotensin II-receptor blocker losartan compared with the angiotensin-converting enzyme inhibitor captopril and conventional triple therapy (TRx) in uremic rats receiving rhEPO therapy.


METHODS
Renal failure was induced by renal mass ablation followed by a 3-week stabilization period. Uremic rats were then divided into five groups with similar systolic BP: vehicle; rhEPO (100 U/kg, subcutaneously, three times per week); rhEPO + losartan (20 mg/kg/d); rhEPO + captopril (20 mg/kg/d); and rhEPO + TRx (reserpine 5 mg/L, hydralazine 80 mg/L, hydrochlorothiazide 20 mg/L). Systolic BP as well as blood and renal parameters were assessed before and after a 3-week treatment period. Renal histology was evaluated at the end of the study.


RESULTS
The uremic rats developed hypertension, anemia, proteinuria, and increased urinary endothelin-1 (ET-1) excretion. The rhEPO corrected the anemia but aggravated the hypertension (P < .01), glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Treatment with losartan, captopril, and the TRx prevented the rhEPO-induced increased in systolic BP. The TRx was less effective in preventing histologic injuries despite similar systolic BP reduction.


CONCLUSIONS
Blockade of the renin-angiotensin system is highly effective in preventing both hypertension and renal histologic damage in rhEPO-treated uremic rats and this benefit seems to extend beyond the antihypertensive effect.
Lebel
Marcel
M
Research Centre, CHUQ, L'Hôtel-Dieu de Québec Hospital and Department of Medicine, Faculty of Medicine, Laval University, Quebec, Canada. marcel.lebel@crhdq.ulaval.ca
Rodrigue
Marie-Eve
ME
Agharazii
Mohsen
M
Larivière
Richard
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000009:adverse effects*; D006830:Hydralazine / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D009392:Nephrectomy; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D012084:Renin-Angiotensin System / Q000187:drug effects; D012110:Reserpine / Q000494:pharmacology; D013997:Time Factors; D014511:Uremia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D011994:Recombinant Proteins; D006852:Hydrochlorothiazide; D004921:Erythropoietin; D006830:Hydralazine; D012110:Reserpine; D002216:Captopril; D019808:Losartan