ABSTRACT
The acute activation of the neurohormonal systems developed to preserve blood pressure and vital organ perfusion at times of stress, appears to be sustained, excessive and deleterious in chronic heart failure. The three types of therapies proven to prolong survival in this disorder, certain beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and an aldosterone antagonist, all attenuate the influences of the sympathetic and renin-angiotensin systems. This chapter will focus on the clinical trials in heart failure and left ventricular dysfunction following myocardial infarction that, pharmacologically, attempt to mitigate the actions of angiotensin II. As a hormone, angiotensin II is a potent vasoconstrictor, which produces renal sodium retention via its hemodynamic effects, an action at the proximal tubule, as well as through the promotion of aldosterone release. Angiotensin II also shifts the thrombosisfibrinolysis balance towards thrombosis. Teleologically, these collective actions of angiotensin II have been characterized as having evolutionary value to provide short-term circulatory support during hemorrhage and conditions of relative dehydration. However, in the setting of an impaired cardiac function, the renin-angiotensin-aldosterone system (RAAS) is also activated in a maladaptive and chronic fashion with apparently detrimental long-term consequences. Over the last 20 years, the discovery of multiple autocrine and paracrine actions of angiotensin II have greatly expanded the potential mechanisms, whereby inhibition of angiotensin II can favorably influence cardiovascular and renal function as well as structure.1,2
The conversion of the inactive decapeptide angiotensin I, to the active octapeptide angiotensin II by the enzyme known both as ACE or kininase II is the key step in the pathway. This enzyme also inactivates bradykinin and, therefore, its inhibition results in both reduced generation of
angiotensin II, as well as an augmentation in local bradykinin levels.3 The net effect in different tissues varies greatly; however, with over two decades of clinical trial experience and an impressive cumulative use profile, there is an extensive experience upon which to base reliable clinical risk/benefit assessments regarding ACE inhibitors in patients with a variety of cardiovascular disorders.
