Renin-angiotensin system and hypertension: The renin-angiotensin system is integral to the mechanisms that sustain hypertension. Hypertensive patients with inappropriately high renin levels have an increased risk of cardiovascular events, and thus there is continuing interest in treating hypertension with drugs that not only reduce blood pressure but also have an inhibitory effect on the renin-angiotensin system.
Inhibitors of the renin-angiotensin system: Angiotensin converting enzyme (ACE) inhibitors decrease blood pressure and ameliorate the symptoms of congestive heart failure. Drugs that selectively block the AT1 angiotensin II receptor are now entering clinical practice for the treatment of hypertension and, very likely, congestive heart failure.
Pharmacologic differences: There are some important theoretical differences between ACE inhibitors and AT1 blockers in their actions on the renin-angiotensin system. ACE inhibitors ostensibly prevent the formation of angiotensin II. However, this action is far from complete, as measurable plasma concentrations of ACE remain during chronic therapy with these agents. AT1 receptor blockers work selectively at the AT1 receptor, leaving the AT2 receptor unaffected. The importance of this selectivity has not yet been established, but AT2 receptors are thought to mediate inhibitory effects on growth. It has been postulated that the selective blockade by this new class of drugs will directly decrease the growth-promoting actions of angiotensin II at the AT1 receptor, while leaving the growth-inhibitory effects of the AT2 receptor unaffected. The clinical relevance of these differing pharmacologic properties of ACE inhibitors and AT1 blockers have not yet been established.
Blood pressure, metabolic and renal effects: AT1 receptor blockers appear to have relatively high trough:peak efficacy ratios compared with ACE inhibitors. However, in patients with essential hypertension compared with normal volunteers, the M value, a measure of glucose clearance and insulin sensitivity, is reduced. Both the ACE inhibitor delapril and the AT1 blocker candesartan have shown a beneficial effect on insulin sensitivity, and candesartan appears to restore the M value to normal. While ACE inhibitors have been shown to have strongly beneficial actions in the kidneys, comparable data are not yet available for AT1 blockers.
Side effects: The relatively common problem of cough observed with ACE inhibitors does not occur with AT1 blockers.
Future work: Future studies must address metabolic and cardiovascular questions that have not yet been answered. It will also be of interest to determine whether the combination of AT1 blockers and ACE inhibitors, especially in more resistant forms of congestive heart failure or hypertension, might confer additive benefits.