OBJECTIVE: To elucidate the mechanisms responsible for the adverse renal effects induced by dual blockade of the renin-angiotensin system (RAS) and the role of salt therein. METHODS: The effects of enalapril, losartan and their combination on blood pressure, renal haemodynamics, renal function and RAS were investigated over a wide range of doses in spontaneously hypertensive rats fed either a low-sodium or a high-sodium diet. RESULTS: In rats fed the low-sodium diet, the losartan-enalapril combination induced the same dose-dependent haemodynamic and hormonal changes as did three- to 10-fold greater doses of enalapril or losartan alone. When a strong decrease (> 50%) in blood pressure was achieved (with 10 mg/kg enalapril plus 10 mg/kg losartan, 100 mg/kg enalapril or 100 mg/kg losartan), a massive renal vasoplegia occurred and renal insufficiency developed. In addition, because of the huge release of renin, angiotensinogen concentrations were reduced, leading to a decrease in intrarenal angiotensins. In rats fed the high-sodium diet, those treated with the enalapril 30 mg/kg plus losartan 30 mg/kg combination, despite complete functional RAS blockade, exhibited smaller decreases in blood pressure and renal resistance, lesser release of renin and angiotensinogen consumption, and a normal renal function. These effects were similar to those produced by 100 mg/kg of enalapril or losartan in rats fed the high-salt diet, or by 10 mg/kg of enalapril or of losartan in rats fed the low-salt diet. CONCLUSIONS: Dual RAS blockade could be either beneficial, when sodium intake is unrestricted, or dangerous, when sodium intake is restricted.
OBJECTIVE: To elucidate the mechanisms responsible for the adverse renal effects induced by dual blockade of the renin-angiotensin system (RAS) and the role of salt therein. METHODS: The effects of enalapril, losartan and their combination on blood pressure, renal haemodynamics, renal function and RAS were investigated over a wide range of doses in spontaneously hypertensiverats fed either a low-sodium or a high-sodium diet. RESULTS: In rats fed the low-sodium diet, the losartan-enalapril combination induced the same dose-dependent haemodynamic and hormonal changes as did three- to 10-fold greater doses of enalapril or losartan alone. When a strong decrease (> 50%) in blood pressure was achieved (with 10 mg/kg enalapril plus 10 mg/kg losartan, 100 mg/kg enalapril or 100 mg/kg losartan), a massive renal vasoplegia occurred and renal insufficiency developed. In addition, because of the huge release of renin, angiotensinogen concentrations were reduced, leading to a decrease in intrarenal angiotensins. In rats fed the high-sodium diet, those treated with the enalapril 30 mg/kg plus losartan 30 mg/kg combination, despite complete functional RAS blockade, exhibited smaller decreases in blood pressure and renal resistance, lesser release of renin and angiotensinogen consumption, and a normal renal function. These effects were similar to those produced by 100 mg/kg of enalapril or losartan in rats fed the high-salt diet, or by 10 mg/kg of enalapril or of losartan in rats fed the low-salt diet. CONCLUSIONS: Dual RAS blockade could be either beneficial, when sodium intake is unrestricted, or dangerous, when sodium intake is restricted.
Authors: Hiddo J Lambers Heerspink; Martin H de Borst; Stephan J L Bakker; Gerjan J Navis Journal: Nat Rev Nephrol Date: 2012-12-18 Impact factor: 28.314
Authors: Bruno Sevá Pessôa; Nils van der Lubbe; Koen Verdonk; Anton J M Roks; Ewout J Hoorn; A H Jan Danser Journal: Nat Rev Nephrol Date: 2012-11-20 Impact factor: 28.314