title: Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke.
abstract: Activation of angiotensin-converting enzyme 2 (ACE2), production of angiotensin-(1-7) [Ang-(1-7)] and stimulation of the Ang-(1-7) receptor Mas exert beneficial actions in various peripheral cardiovascular diseases, largely through opposition of the deleterious effects of angiotensin II via its type 1 receptor. Here we considered the possibility that Ang-(1-7) may exert beneficial effects against CNS damage and neurological deficits produced by cerebral ischaemic stroke. We determined the effects of central administration of Ang-(1-7) or pharmacological activation of ACE2 on the cerebral damage and behavioural deficits elicited by endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO), a model of cerebral ischaemia. The results of the present study demonstrated that intracerebroventricular infusion of either Ang-(1-7) or an ACE2 activator, diminazine aceturate (DIZE), prior to and following ET-1-induced MCAO significantly attenuated the cerebral infarct size and neurological deficits measured 72 h after the insult. These beneficial actions of Ang-(1-7) and DIZE were reversed by co-intracerebroventricular administration of the Mas receptor inhibitor, A-779. Neither the Ang-(1-7) nor the DIZE treatments altered the reduction in cerebral blood flow elicited by ET-1. Lastly, intracerebroventricular administration of Ang-(1-7) significantly reduced the increase in inducible nitric oxide synthase mRNA expression within the cerebral infarct that occurs following ET-1-induced MCAO. This is the first demonstration of cerebroprotective properties of the ACE2-Ang-(1-7)-Mas axis during ischaemic stroke, and suggests that the mechanism of the Ang-(1-7) protective action includes blunting of inducible nitric oxide synthase expression.
authors.affiliation: Department of Physiology & Functional Genomics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610-0274, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Mecca
authors.forename: Robert W
authors.initials: RW
authors.lastname: Regenhardt
authors.forename: Timothy E
authors.initials: TE
authors.lastname: O'Connor
authors.forename: Jason P
authors.initials: JP
authors.lastname: Joseph
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Katovich
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
mesh_terms: D000803:Angiotensin I / Q000627:therapeutic use*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D019332:Endothelin-1; D004789:Enzyme Activation; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology; D020521:Stroke / Q000517:prevention & control*
chemical_list: C092006:7-Ala-angiotensin (1-7); D019332:Endothelin-1; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000803:Angiotensin I; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); C003915:diminazene aceturate; D004133:Diminazene