Blockade of the renin angiotensin cascade--an overview

It is now possible to block the renin angiotensin system at several points in the cascade. Apart from the Angiotensin Converting Enzyme (ACE) inhibitors, both orally active renin inhibitors and angiotensin II receptor antagonist (ATA) are under active development and clinical investigation. ACE inhibitors can be regarded as relatively non-specific as the enzyme has many possible peptide substrates including bradykinin. There may also be alternative, non ACE pathways for the generation of angiotensin II, particularly in tissues. Renin inhibition can be regarded as a more selective blockade. Renin inhibitors have a long history but the recent development of orally active, non peptide inhibitors have made them a clinical reality. The current available renin inhibitors have limited bioavailability in man. To date few studies in humans have been reported. These preliminary studies suggest that their hypotensive efficacy may be limited by a reactive hyper reninaemia. Blocking the AT II receptor acts on the final step. Several ATA are undergoing extensive clinical trials but only losartan has been licensed in any country to date. Most of the ATAS are specific for the AT1 receptor subtype and do not block the AT2 receptor. A concern is that the increased AT II levels that occurs after losartan may act on the unprotected AT2 receptors with unknown consequences. Studies with ATA antagonists have demonstrated that they lower blood pressure. Other limited studies in man suggest they share many of the benefits of ACE inhibitors including regression of left ventricular hypertrophy, decrease in sympathetic activity, increase in insulin sensitivity and reduction in proteinuria. To date cough does not appear to be an adverse effect. To date the theoretical differences in blocking the RAS at different stages have not eventuated in clinical manifestations.