RAAS inhibition and mortality in hypertension: from pharmacology to clinical evidence.

PHARMACOLOGICAL EVIDENCE FOR RAAS INHIBITION ACE inhibitors and ARBs inhibit the RAAS in distinct ways. ACE inhibitors prevent the enzyme ACE from converting angiotensin I into angiotensin II (Table 1) [7, 8]. Angiotensin II is a vasoconstrictor that causes a host of deleterious effects, including vascular damage at the endothelial and structural levels [9]. Angiotensin II is an important cause of heart, brain, and kidney damage, as well as a modulator of aldosterone, a hormone that increases BP by increasing sodium reabsorption, water retention, and blood volume. Pathological outcomes induced by angiotensin II include myocardial infarction (MI), heart failure, stroke, and renal failure. ACE inhibition impairs angiotensin II production, resulting in a number of positive CV benefits. Attenuation of angiotensin II reduces levels of proinflammatory markers and prevents atherogenesis. It also inhibits fibrosis and reduces endothelial dysfunction [9]. Decreases in the concentrations of plasminogen activator inhibitor 1 and tissue factor, caused by the reduction of angiotensin II levels, inhibit thrombosis [8]. For these positive inhibitory effects to occur, it is important that local ACE is inhibited. The advantages of angiotensin II reduction by ACE inhibition are substantial, but may be compromised in the long term because of ‘escape’ effects related to angiotensin II and aldosterone [10]. Disrupted negative feedback mechanisms cause renin and angiotensin I concentrations to rise, eventually leading to angiotensin II escape when non-ACE enzymes, such as chymase, convert angiotensin I to angiotensin II [11]. Similarly, aldosterone escape occurs after long-term ACE inhibitor therapy, due to progressive elevation of aldosterone levels. Given this scenario, one might expect ACE inhibitors to lose all their efficacy over the long term, but this is not the case, thanks to a complementary mechanism of action related to ACE inhibition. By inhibiting ACE, ACE inhibitors also increase concentrations of the vasodilatory peptide bradykiINTRODUCTION The renin–angiotensin–aldosterone system (RAAS) regulates the body’s haemodynamic equilibrium, circulating volume, and electrolyte balance, and is a key therapeutic target in hypertension, the world’s leading cause of premature mortality [1]. Hypertensive disorders are strongly linked with an overactive RAAS [2], and RAAS inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are routinely used to treat high blood pressure (BP) [3]. BP reduction is one of the main goals of current European hypertension guidelines [4]. Oral ACE inhibitors, the oldest category of RAAS inhibitor, were commercially released in the early 1980s, more than a decade before the first ARBs became available [5]. The introduction of ACE inhibitors heralded major changes in the way hypertension and cardiovascular (CV) disease were treated. Although the decision of the medical community to replace older ACE inhibitors with more modern ARBs in the 1990s was debatable, it did nevertheless allow scientists to learn more about the angiotensin receptors involved in RAAS stimulation. This and much else of value have been discovered since RAAS inhibitors first became available, but some surprising gaps in our knowledge still exist. Until recently, the effect of RAAS inhibition on mortality in hypertension was unknown. This question was recently addressed by a meta-analysis of randomised controlled trials in populations who received contemporary antihypertensive medication [6]. The results of this meta-analysis have helped elucidate the long-term consequences of treatment with RAAS inhibitors on mortality in hypertension. This article will consider the differences between RAAS inhibitors in terms of their pharmacological and clinical effects, and analyse the impact of the main types of RAAS inhibitor, ACE inhibitors and ARBs, on mortality reduction in hypertensive patients with reference to this latest metaanalysis [6].