Angiotensin II type 1 receptor blockade: a novel therapeutic concept

Angiotensin II type 1 (AT(1)) receptor blockers, such as candesartan, are a ttractive alternatives to ACE inhibitors in the treatment of hypertension a nd cardiovascular disease. Although angiotensin-converting enzyme (ACE) inh ibitors are able to suppress the renin-angiotensin system (RAS), their mech anism of action may limit their clinical utility in the treatment of hypert ension. For example, they act as competitive inhibitors of ACE. This means that their effects can be overcome by high levels of angiotensin I, which o ccur after ACE inhibition due to removal of the negative feedback effect of angiotensin II on renal renin release. ACE inhibitors are also unable to b lock the production of angiotensin II by non-ACE-mediated pathways. Further more, ACE is not a specific enzyme. Its inhibition therefore has effects on other substances, such as bradykinin, leading to the class-specific side e ffects associated with ACE inhibitors. Candesartan, on the other hand, bind s insurmountably to the AT(1) receptor, thereby providing more complete blo ckade of the negative cardiovascular effects of angiotensin II than is poss ible with ACE inhibitors. The specificity of AT(1)-receptor blockade also e nsures that efficacy is achieved without inducing the side effect of cough that results from the non-specific consequences of ACE inhibition. Preclini cal and early clinical studies demonstrate that AT(1)-receptor blockers pro duce at least the same degree of target-organ protection as has been demons trated for ACE inhibitors. Additional benefits of AT(1)-receptor blockers m ay arise from the fact that, unlike ACE inhibitors, they do not prevent the activity of angiotensin II on AT(2)-receptors in the heart, which is thoug ht to reduce cardiac remodelling. From a mechanistic perspective, therefore , AT(1)-receptor blockers appear to have advantages over ACE inhibitors, in terms of a more complete blockade of angiotensin II effects, while also av oiding the specific side effects associated with ACE inhibition.