Molecular interactions of vasoactive systems in cardiovascular damage

The renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS) are important in the aetiology of hypertension and the pathogenesis of cardiac and renal damage associated with elevated blood pressure. While angiotensin II acts by increasing blood pressure and supporting end-organ damage, kinins have an opposite protective effect. The two systems interact on many levels. Angiotensin-converting enzyme (ACE) activates angiotensins and inactivates kinins. ACE inhibitors therefore exert their organ-protective action via both systems, as they block the deleterious RAS and potentiate the protective KKS. Furthermore, ACE may directly interact with the kinin B2 receptor and ACE inhibitors, thereby eliciting a resensitization of this receptor following agonist-induced desensitization. Recently, a functional heterodimer of AT1 and B2 receptors has also been demonstrated. Moreover, kallikreins may be involved in the activation of prorenin and in the signalling pathway of angiotensin AT2 receptors. Because of the multitude of interactions, any therapeutic intervention into one of the two peptide systems will automatically lead to an alteration in the other. This double action is utilized by drugs such as ACE inhibitors to provide unprecedented effectiveness in hypertension and associated cardiac and renal damage.