Revisiting the Brain Renin-Angiotensin System-Focus on Novel Therapies

Although an independent brain renin-angiotensin system is often assumed to exist, evidence for this concept is weak. Most importantly, renin is lacking in the brain, and both brain angiotensinogen and angiotensin (Ang) II levels are exceptionally low. In fact, brain Ang II levels may well represent uptake of circulating Ang II via Ang II type 1 (AT₁) receptors.

Nevertheless, novel drugs are now aimed at the brain RAS, i.e., aminopeptidase A inhibitors should block Ang III formation from Ang II, and hence diminish AT₁ receptor stimulation by Ang III, while AT₂ and Mas receptor agonists are reported to induce neuroprotection after stroke. The endogenous agonists of these receptors and their origin remain unknown. This review addresses the questions whether independent angiotensin generation truly occurs in the brain, what its relationship with the kidney is, and how centrally acting RAS blockers/agonists might work.