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 th e renin-angiotensin system (RAS) cardioprotection due to vasodilative (reduction of blood pressure, afterload reduction), antiproliferative (reduced cell growth, reduction of ''vascular'' and/or ''ventricular r emodeling'', reduced formation of extracellular matrix), as well as an tiadrenergic 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-inhi bitors by experimental and clinical studies but except for the treatme nt of arterial hypertension and few preliminary reports concerning the treatment of cardiac dysfunction, no comparable data are available fo r AT(1)-receptor antagonists. To date, an antithrombotic and profibrin olytic action could only be demonstrated for ACE-inhibitors. This effe ct has been discussed to be responsible for the improvement of longter m prognosis in patients with coronary artery disease. Despite the simi lar spectrum of action there exist important differences between ACE-i nhibitors and AT(1)-receptor antagonists that might underline the need of an individual use of these drugs: the dual action of ACE-inhibitor s on the RAS and the kinin system bears many benefits but has been als o shown to be accompanied by side-effects, mainly chronic dry cough, i n a relatively high percentage of patients thus leading to discontinua tion of therapy in 8-14 %. This respective side-effect can be prevente d by the use of AT(1)-receptor antagonists. It has been discussed whet her 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. D ue to their direct action, AT(1)-receptor-blockers might also be of hi gh effectiveness for the treatment of severe heart failure. A combinat ion of the ACE-inhibitor-mediated activation of the kinin-system with the more specific blockade of AT(1)-receptors by AT(1)-receptor antago nists might be of benefit and is currently under investigation. Finall y, it has been discussed that the increased AT II concentration in cas e of AT(1)-receptor-blockade activates AT(2)-receptor-mediated mechani sms thus leading to an additive vasoprotective effect.