Angiotensin II type 1 receptor blockers.

In the 1970s, a series of observations demonstrated that angiotensin II has deleterious effects on the heart and kidney and that patients with high levels of plasma renin activity are at a higher risk of developing stroke or myocardial infarction than those with low plasma renin activity.1,2 Thereafter, the development of pharmacological probes that block the renin-angiotensin system helped define the contribution of this system to blood pressure control and to the pathogenesis of diseases such as hypertension, congestive heart failure, and chronic renal failure. Thus, the concept of treating hypertension and congestive heart failure by a specific blockade of the renin-angiotensin system was first established with the use of saralasin, a nonselective peptidic antagonist of angiotensin II receptors.3–9 With saralasin, it became possible to demonstrate that angiotensin II receptor blockade, alone or in combination with salt depletion, lowers blood pressure in hypertensive patients and improves systemic hemodynamics in patients with congestive heart failure.3–10 However, saralasin had many drawbacks. Because it is a peptide, it had to be administered intravenously. This characteristic limited its use to hours or a few days at maximum. In addition, at higher doses, saralasin had some partial agonist, angiotensin II–like effects. The next major breakthrough in the understanding of the renin-angiotensin system was triggered by the development of orally active angiotensin-converting enzyme (ACE) inhibitors.10–15 Studies performed with these agents rapidly confirmed and reinforced the seminal clinical observations made with saralasin. ACE inhibitors are now recognized as an important therapeutic step to control blood pressure in hypertensive patients and to reduce morbidity and mortality in patients with congestive heart failure.16 In addition, because of their ability to lower proteinuria, ACE inhibitors have become an essential component of the treatment of chronic renal diseases to delay the progression of renal failure.17 ACE inhibitors are also very effective in reducing cardiovascular morbidity and mortality in patients with a high cardiovascular risk profile, including diabetics.18 ACE is an enzyme with multiple effects, not all of which are mediated through angiotensin receptors. Thus, the hope has been that angiotensin II receptor blockers would produce more specific actions and fewer side effects than ACE inhibitors. When ACE inhibitors became available, the more specific approach of blocking angiotensin II receptors was abandoned. Nevertheless, research continued. This resulted in the most recent therapeutic development of specific, nonpeptide, orally active angiotensin II receptor antagonists.19