Journal of Human Hypertension (2000) 14, Suppl 2, S23–S31 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh Blocking the tissue renin-angiotensin system: the future cornerstone of therapy T Unger1, M Azizi2 and GG Belz3 1Institute of Pharmacology, Christian Albrechts University, Hospitalstra␤e 4, 24105 Kiel, Germany; 2Centre D’Investigations Cliniques, Hoˆ pital Broussais, 96 Rue Didot – 75674, Paris Cedex 14, France; 3Zentrum fuer Kardiovaskulaere Pharmakologie, ZeKaPha GmbH, Mathildenstra␤e 8, D-55116, Mainz-Wiesbaden, Germany The development of angiotensin-converting enzyme antagonist, is characterised by its tight binding to and inhibitors and selective angiotensin type 1 (AT1)- slow dissociation from the AT1 receptor, and high antag- receptor antagonists has provided new insights into onistic potency, resulting in long-lasting antagonistic understanding the mechanism of the renin-angiotensin effects. It is anticipated that these pharmacological system (RAS) in the pathophysiology of cardiovascular characteristics may bring additional benefits to patients, disease. There is good evidence from meta-analyses not only for the management of essential hypertension that shows that inhibition of the RAS achieves organ but also for the management of end-organ damage. protection features that go beyond blood pressure con- Journal of Human Hypertension (2000) 14, Suppl 2, S23– trol. Candesartan cilexetil, a new angiotensin II receptor S31 Keywords: renin-angiotensin system; angiotensin-converting enzyme inhibitor; angiotensin type 1 receptor; angiotensin receptor antagonist; candesartan cilexetil Introduction Blocking the RAS in essential Hypertension is a major risk factor for myocardial hypertension infarction, stroke, and renal and peripheral vascular Angiotensin II, the key effector peptide of the RAS, disease. Epidemiological studies have found a direct exerts a variety of actions in the regulation of arterial linear correlation between the risk of cardiovascular blood pressure and the maintenance of fluid and disease and blood pressure levels. Long-term elev- electrolyte homeostasis. Blood pressure is raised by ations in blood pressure are associated with a direct pressor action, increased sympathetic trans- hypertrophy, hyperplasia and remodelling of the mission, water retention (via direct action on heart, as well as vascular and renal damage. While sodium reabsorption, or indirectly via increased some of these changes are compensatory adaptations aldosterone release) and altered renal haemodynam- to the increased workload associated with raised ics. Angiotensin II also acts centrally to induce thirst blood pressure, structural remodelling of the kidney, and drinking behaviour, to attenuate the barorecep- heart and vasculature may also occur independently tor reflex and to release arginine vasopressin and of blood pressure levels.1 It would appear that the other hormones such as adrenocorticotrophic hor- renin-angiotensin system (RAS) plays a central role mone and oxytocin.5,6 in the acute and chronic development of cardio- Blockade of the RAS using ACE inhibitors or angi- vascular disease. Yet, it is only recently, with the otensin II receptor antagonists (AIIRAs) results in an development of angiotensin-converting enzyme acute hypotensive response in sodium-depleted (ACE) inhibitors and selective angiotensin type 1 animals or humans. In conditions associated with (AT ) receptor antagonists, that the full significance 1 elevated plasma angiotensin II levels, such as of RAS in the acute and chronic development of car- experimental or clinical renovascular hypertension diovascular disease has been realised. There is good and congestive heart failure, these agents bring evidence from meta-analyses that shows that inhi- about a marked depressor response.7 In most acute bition of the RAS achieves organ protection features studies, the magnitude of the depressor response that go beyond blood pressure control.2–4 can be predicted by the pre-treatment plasma levels This paper reviews the possible mechanisms of of renin and consequently of angiotensin II, indicat- ACE inhibition and angiotensin II receptor antagon- ing a causal relationship.7 ism in organ protection and hypothesises on the Although the acute blood pressure-lowering possible clinical benefits that may be achievable effects of RAS inhibition correlate with initial with prolonged angiotensin II receptor blockade. plasma renin activity, the chronic response bears little relation to pre-treatment levels.7 Both ACE inhibitors and AIIRAs can lower blood pressure Correspondence: Professor T Unger, Institute of Pharmacology, levels in hypertensive patients whose plasma renin Christian Albrechts University, Hospitalstra␤e 4, 24105 Kiel, levels are normal or even low, but the magnitude of Germany. Tel: + 49 431 597 3500, Fax: + 49 431 597 3522 the antihypertensive response is often less pro- Blocking tissue renin-angiotensin system T Unger et al S24 nounced in patients with low renin levels. While heart failure and atherosclerosis, the expression and circulating angiotensin levels have an important activity of ACE may be dramatically increased.18,25–27 endocrine function in acute volume and blood Normally absent from vascular smooth muscle, pressure homeostasis, the tissue RAS within the recent immunohistochemical evidence indicates brain, heart, kidney, adrenals and blood vessels acts that ACE can be detected in migrated macrophages as a regulator or amplifier of local function.8 Angiot- and smooth muscle cells of atherosclerotic coronary ensin II, which is released by vascular cells, has both arteries during the progression of atherosclerosis, an autocrine function (causing endothelial dysfunc- and in the early healing processes following percu- tion and smooth muscle hypertrophy) and a parac- taneous transluminal coronary angioplasty rine function (influencing smooth muscle tone).8 It (PTCA).28 has been postulated that abnormal tissue RAS activi- Angiotensin I is not the only substrate for ACE, ties are contributors to the development and mainte- which also degrades bradykinin and a number of nance of essential hypertension.8,9 Both ACE inhibi- other peptides (Figure 1).29 Bradykinin, produced tors and AIIRAs prevent and/or reverse most of the locally within tissues, is thought to have beneficial vasculature changes in experimental and clinical effects promoting vasodilatation, natri/diuresis and hypertension. antiremodelling. In animal experiments, the abilities of ACE inhibitors to potentiate kinins as well as ACE inhibition and end-organ damage inhibit the formation of angiotensin II have both been demonstrated to contribute to organ protection Intervention with ACE inhibitors, introduced 20 in various models of cardiovascular disease.30–32 years ago as antihypertensive agents, has become However, it is still not clear to what degree the one of the most successful therapeutic approaches potentiation of kinins adds to the beneficial effects for reducing left ventricular mass,2 decreasing over- of ACE inhibitors in clinical practice. It seems that all mortality and death from chronic heart failure,10 an increase in bradykinin contributes to the short- improving the outcome for patients with ventricular term effects of ACE inhibition on blood pressure.33 systolic dysfunction and symptomatic heart However, the effect of ACE inhibitors on bradykinin failure,11 reducing post-myocardial infarction mor- does not appear to contribute substantially to the tality,12 retarding the progression of renal insuf- long-term effects of the drug, at least not in patients ficiency in insulin-dependent diabetes mellitus with congestive heart failure.34 (IDDM), improving renal function in IDDM and The local production of angiotensin II augmenting retarding the progression of non-diabetic chronic a tissue-specific response independent of the circu- renal disease.13–15 ACE inhibitors have recently been latory RAS presents a powerful new model for the shown to reduce the rate of death, myocardial pathogenesis of cardiovascular disease. This theory infarction and stroke in a broad range of patients is supported by the recent identification of local with a high cardiovascular risk at baseline.16 In eld- tissue enzymes such as chymase in the heart and erly hypertensive patients, ACE inhibitors have been vasculature which indicate a role of ACE-inde- shown to reduce the incidence of fatal and non-fatal pendent pathways in the production of angiotensin cardiovascular events17 to the same extent as con- at a local tissue level.35 In addition, other proteases ventional therapy with diuretics or ␤-blockers. such as cathepsin G36–38 and elastases39 are thought Research into mechanisms of ACE inhibition in end- to enhance angiotensin II generation locally at sites organ damage has focused on the dual role of the of inflammation and tissue injury. circulating RAS as well as the tissue RAS on end- Although it is still controversial whether active organ damage.8,18 renin is derived directly from the kidney or syn- Angiotensin II is recognised as a growth-promot- thesised locally in the heart or blood vessels,40,41 all ing factor that contributes in an autocrine/paracrine other major components of the RAS have been local- fashion to structural alterations in various organs, ised in the heart and blood vessels. Thus, both circu- most notably the heart, vasculature and kidneys.6,19 lating and tissue angiotensins play important roles It is also involved in cardiac left ventricular