Combined blockade of the renin-angiotensin system

Blockade of the renin-angiotensin system (RAS) with angiotensin-converting-enzyme (ACEI) inhibitors or angiotensin II receptor blockers (ARB) has become a major therapeutic tool. Due to internal counter-regulation, however, this system cannot be fully blocked by targeting only one of its components. Instead of increasing the doses of an ACEI, an ARB or a renin inhibitor, blocking RAS at two successive levels neutralizes the consequences of internal counter-regulation and thus provides a more complete blockade with more pronounced biological effects. Additive effects on blood pressure lowering and on renin secretion during combined administration of RAS blockers were first demonstrated in normotensive subjects and in various experimental models of hypertension, heart failure and renal failure. Although combined RAS blockade provided an additional hemodynamic response and more complete neutralization of the cellular effects of angiotensin II, no benefit was observed in terms of cardiovascular or renal protection in heart disease (heart failure, post-myocardial infarction, high vascular risk) or kidney disease (diabetic nephropathy). Moreover, more complete RAS blockade is risky in conditions where blood pressure and renal perfusion are renin-dependent (renal failure and hypotension) and also in hypoaldosteronism (hyperkalemia). The European, French and US. health agencies have contraindicated combined RAS blockade because of its unfavorable risk-benefit balance, especially in patients with diabetes or renal failure.