Pathophysiologic mechanisms of the renin-angiotensin-system and the pharmacological influence of ACE-inhibitors or angiotensin II type 1 receptor antagonists in cardiovascular disease

As a net effect of ACE-inhibitors and AT(1)-receptor antagonists on the renin-angiotensin system (RAS) cardioprotection due to vasodilative (reduction of blood pressure, afterload reduction), antiproliferative (reduced cell growth, reduction of ''vascular'' and/or ''ventricular remodeling'', reduced formation of extracellular matrix), as well as antiadrenergic actions and due to the stimulating effect on natriuresis, reduction of blood pressure, preload reduction can be expected. These aims of therapy have mostly been confirmed for the action of ACE-inhibitors by experimental and clinical studies but except for the treatment of arterial hypertension and few preliminary reports concerning the treatment of cardiac dysfunction, no comparable data are available for AT(1)-receptor antagonists. To date, an antithrombotic and profibrinolytic action could only be demonstrated for ACE-inhibitors. This effect has been discussed to be responsible for the improvement of longterm prognosis in patients with coronary artery disease. Despite the similar spectrum of action there exist important differences between ACE-inhibitors and AT(1)-receptor antagonists that might underline the need of an individual use of these drugs: the dual action of ACE-inhibitors on the RAS and the kinin system bears many benefits but has been also shown to be accompanied by side-effects, mainly chronic dry cough, in a relatively high percentage of patients thus leading to discontinuation of therapy in 8-14 %. This respective side-effect can be prevented by the use of AT(1)-receptor antagonists. It has been discussed whether the incomplete action of ACE-inhibitors on AT(1)-receptor-mediated effects is at least in part responsible for the efficacy of this drug which is relatively high (75-80 %) as compared to other substances. Due to their direct action, AT(1)-receptor-blockers might also be of high effectiveness for the treatment of severe heart failure. A combination of the ACE-inhibitor-mediated activation of the kinin-system with the more specific blockade of AT(1)-receptors by AT(1)-receptor antagonists might be of benefit and is currently under investigation. Finally, it has been discussed that the increased AT II concentration in case of AT(1)-receptor-blockade activates AT(2)-receptor-mediated mechanisms thus leading to an additive vasoprotective effect.