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Haemodynamic effects of dual blockade of the renin???angiotensin system in spontaneously hypertensive rats

2004; Lippincott Williams & Wilkins; Volume: 22; Issue: 3 Linguagem: Inglês

10.1097/00004872-200403000-00026

1473-5598

Christine Richer-Giudicelli, Val rie Domergue, Marie-Fran oise Gonzalez, Erij Messadi, Michel Azizi, Jean-Fran ois Giudicelli, Jo l M nard,

Sodium Intake and Health

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.