The renin-angiotensin-aldosterone system (RAAS) is largely responsible for maintaining the body's fluid homeostasis. Operating around a genetically determined "set point" in each individual, this system exquisitely modulates the resistance of the circulatory system to the pumping output of the heart. One of the fundamental steps by which the RAAS exerts this control is through conversion of the inactive hormone angiotensin I to the powerful vasoconstrictor angiotensin II. What happens when this carefully regulated system is out of balance, and how can a healthy state be restored?
When an individual's circulatory system is no longer operating around its physiologic set point (ie, in a healthy balance), it is usually because there is fluid overload and/or excessive vasoconstriction. The immediate result will be hypertension ("high blood pressure"); over the longer term, the result may be various manifestations of cardiovascular disease and, eventually, heart failure
To treat this condition, it would be beneficial to curtail the activity of the body's powerful vasoconstrictor, angiotensin II. This can be done in 2 ways:
By blocking the conversion of angiotensin I to angiotensin II, through inhibition of the enzyme that catalyzes that conversion, using angiotensin-converting enzyme (ACE) inhibitors.
By blocking binding of the circulating angiotensin II to its receptors in the walls of the circulatory system, using angiotensin II (type 1) receptor blockers (ARBs).
Although ACE inhibitors were originally developed as an antihypertensive therapy, a series of trials conducted in the early 1990s established that ACE inhibitors offer powerful therapy in post-MI patients as well as in heart failure, and they have become the guideline-mandated basis of therapy for these disorders. Through their high-level interruption of the conversion of Ang I to Ang II, however, ACE inhibitors exert a broad systemic effect, and conceptually it would be useful to create a more targeted blockade of the actions of Ang II. To achieve this more focused therapeutic goal, ARBs were developed to act selectively by blocking binding of Ang II to the angiotensin type 1 (AT1) receptors.
By acting at the receptor level, ARBs provide more complete blockade of the RAAS than ACE inhibitors do, and they do not potentiate bradykinins, which are thought to mediate the ACE inhibitor-induced cough. ARBs have effects similar to those of the ACE inhibitors with regard to hemodynamics, neurohormones, and exercise capacity, and in some patients they may be better tolerated. A series of large-scale clinical trials have established the efficacy of ARBs as an add-on or even as an alternative to ACE inhibitors for the treatment of both hypertension and heart failure, and the drugs are under investigation for the treatment of renal disease.