[Combined blockade of the renin-angiotensin system]

In view of the internal counter-regulation mechanisms of the renin-angiotensin system (RAS), complete blockade would not seem to be possible if only one of its components is targeted. Instead of increasing the dosage of an angiotensin converting enzyme (ACE) inhibitor or that of an angiotensin II antagonist (AA), blockade of the system at two different levels by neutralising the internal counter-regulation mechanism could provide more effective blockade and, therefore, more pronounced biological effects. For this reason, the authors undertook two studies in a model of mild salt depletion of a normotensive subject, which showed additive effects on the lowering of the blood pressure and renin secretion during combined administration of captopril and losartan, then enalapril and losartan. There was no additive effect on plasma aldosterone levels. The administration of the ACE inhibitor neutralised the expected increases in plasma Angiotensin II values due to the losartan. All combinations of ACE inhibitor and AA were tested in spontaneous hypertensive rats using a dosage scale from 1 to 30, the results of which showed the beneficial effects of combined blockade on left ventricular mass and the deleterious effects on renal function when blockade of the RAS is too complete. Based on the results obtained in normotensive subjects and homogeneous groups of hypertensive animals, the authors conclude that low doses of an AA and of an ACE inhibitor is more effective in lowering the blood pressure than higher doses of each drug administered separately. How can these results be applied clinically in hypertension and cardiac failure? The choice between increasing the dose of each of the two drugs or the association of low doses of both drugs will depend more on the tolerance of each therapeutic strategy than on the efficacy. The choice between the two strategies will also depend on the demonstration of consequences specific to each modality of inhibition of the system, especially with respect to the effects of accumulation of bradykinin and to stimulation of type 2 receptors. The additive effects of a combined treatment should be validated by repeated administration in hypertensive patients.