The renin-angiotensin system in the brain: possible therapeutic implications for AT(1)-receptor blockers

Biochemical, physiological and functional studies suggest that the brain renin-angiotensin system (RAS) is regulated independently of the peripheral RAS. The classical actions of angiotensin II in the brain include blood pressure control, drinking behaviour, natriuresis and the release of vasopressin into the circulation. At least two subtypes of G-protein coupled receptors, the AT(1) and the AT(2) receptor, have been identified. Most of the classic actions of angiotensin II in the brain are mediated by AT(1) receptors. The AT(2) receptor is involved in brain development and neuronal regeneration and protection. Additionally, AT(2) receptors can modulate some of the classic angiotensin II actions in the brain. Selective non-peptide AT(1) receptor blockers, applied systemically, have been shown to inhibit both peripheral and brain AT(1)receptors. In genetically hypertensive rats, inhibition of brain AT(1) receptors may contribute to the blood pressure lowering effects of AT(1) receptor blockers. Animal studies have shown that AT(1) receptor antagonists enable endogenous angiotensin II to stimulate neuronal regeneration via activation of AT(2) receptors. In animal models, inhibition of the brain RAS proved to be beneficial with respect to stroke incidence and outcome. Blockade of brain and cerebrovascular AT(1) receptors by AT(1) receptor blockers prevents the reduction in blood flow during brain ischaemia, reduces the volume of ischaemic injury and improves neurological outcome after brain ischaemia. This paper reviews the actions of angiotensin II and its receptors in the brain, and discusses the possible consequences of AT(1) receptor blockade in neuroprotection, neuroregeneration, cerebral haemodynamics and ischaemia.