The renin-angiotensin system (RAS) is well recognized for its importance in regulation of BP, electrolyte balance and vascular growth. Pharmacological suppression of the RAS, through ACE inhibition and/or
angiotensin receptor blockade, is a proven effective therapeutic approach to the treatment of a range of
cardiovascular diseases.
Renin is the
enzyme that catalyzes the first and rate-limiting step of RAS, the cleavage of
angiotensinogen to
angiotensin I (A-I). A-I is then further converted by ACE to the biologically active
vasoconstrictor, A-II. Interruption of the generation of A-II by
renin inhibitors at this highly specific initial step of the cascade would be expected to have similar but not identical effects to those of the already well established RAS antagonists. Due to the lack of effective alternative
enzyme pathways, blockade of A-II production may be more effective with
renin inhibition than with ACE inhibition, and because of the high specificity of
renin for only one substrate, namely
angiotensinogen, adverse effects would be expected to be less frequent. It is currently unclear whether blockade of
angiotensin II type 1 receptors (AT(1)), leaving other A-II receptors unblocked, is preferable to the reduction in plasma and tissue A-II levels achieved with either ACE or
renin inhibition. The development of early peptidic and
peptidomimetic renin inhibitors was hampered by problems with oral bioavailability and high costs of synthesis. However recent work has led to the synthesis of a potent non-peptidic inhibitor of
renin,
aliskiren, which has acceptable oral bioavailability. This
renin inhibitor has been shown to effectively reduce A-II levels in normal volunteers and to lower BP in patients with mild to moderate
hypertension. It appears likely that
aliskiren is the first of a new class of agents that may prove useful in the management of patients with nephropathy,
heart failure and
atherosclerosis in addition to
hypertension.