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Renin-angiotensin system blockade: to what extent?

Two experimental studies reported in this issue of the journal [1,2] describe different methods for blocking the renin–angiotensin system (RAS) and analyse the cardiac and renal consequences of these methods. Both reports consider the most effective way to inhibit the RAS either by an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor (AT1R) antagonist, or their combination. These two studies have similar methodological strengths: a wide range of studied doses, a sufficient number of animals per group, and the selection of robust end-points. The synergistic effects on blood pressure and left ventricular mass (LVM) of treatment combining an ACE inhibitor and AT1R antagonist at various doses are precisely documented by the two studies. They reach similar conclusions concerning the candesartan and ramipril combination [1], and the losartan and enalapril combination [2]. The German study makes two specific contributions. (i) A demonstration that the synergistic effects on blood pressure and LVM reduction observed are due to the combination of an ACE inhibitor with an AT1R antagonist, blocking the RAS at two successive sites along the renin-dependent angiotensin II-producing pathway. No such synergism is observed by simply combining a RAS blocker with an antihypertensive drug, as the T-calcium-channel blocker mibefradil, for example, does not enhance the effects of candesartan in the way that ramipril does. (ii) When high doses of each single site RAS blocker are combined, the synergistic and, even more, the additive effects of the combination are no longer observed. This was already demonstrated by Morgan et al. [3] in acute experiments. The French study investigated the influence of salt intake on blood pressure and LVM responses to various doses of losartan, enalapril and their combination in spontaneously hypertensive rats (SHR). Doses of an ACE inhibitor and an AT1R antagonist in a combination that was one-third to one-tenth of those used in a single-drug treatment were found to have the same haemodynamic and trophic effects as the highest doses of a single drug (100 mg/kg). Independently of the site of RAS blockade, all haemodynamic changes are qualitatively similar and proportional to the intensity of the blockade. This study documents the renal risk of treatment with a 10 mg/kg enalapril–losartan combination in SHR with low salt intake (0.05% Naþ). Such a risk has already been reported in SHR with normal salt intake (0.3%) [4]. Finally, the results indicate that, on a high sodium intake (2%), haemodynamic effects similar to those observed a low sodium intake are observed, but the doses of the RAS blockers required are higher. Above a certain dose, the effect appears to be maximal, and reaches a plateau. The 10 mg/kg enalapril–losartan combination, poorly tolerated on a low-salt diet, is well tolerated on a high sodium intake and is almost as effective as the 30 mg/kg combination. By contrast, no plateau effect is found when vascular reactivity to exogenous angiotensin I and II is analysed. However, we still ignore whether and to what extent this pharmacological response is related with the blood pressure-independent beneficial effect of neutralization of the direct tissue effects of angiotensin II on target organs. This observation could be interpreted, with caution, as evidence that it is possible to obtain supplementary beneficial effects by reinforcing the RAS blockade, even in the absence of a supplementary lowering effect on blood pressure [5].