Enzymatic pathways of the brain renin–angiotensin system: Unsolved problems and continuing challenges

The brain renin–angiotensin system continues to be enigmatic more than 40 years after the brain was first recognized to be a site of action of angiotensin II. This review focuses on the enzymatic pathways for the formation and degradation of the growing number of active angiotensins in the brain. A brief description and nomenclature of the peptidases involved in the processing of angiotensin peptides in the brain is given. Of primary interest is the array of enzymes that degrade radiolabeled angiotensins in receptor binding assays. This poses major challenges to studies of brain angiotensin receptors and it is debatable whether an accurate determination of brain angiotensin receptor binding kinetics has yet been made. The quandary facing the investigator of brain angiotensin receptors is the need to protect the radioligand from metabolic alteration while maintaining the characteristics of the receptors in situ. It is the tenet of this review that we have yet to fully understand the binding characteristics of brain angiotensin receptors and the extent of their distribution in the brain because of our inability to fully protect the angiotensins from metabolic alteration until equilibrium binding conditions can be attained.