title: Cerebroprotective effect of angiotensin IV in experimental ischemic stroke in the rat mediated by AT(4) receptors.
abstract: Recent studies have reported potential roles of angiotensins in an adaptative physiological mechanism of protection against cerebral ischemia-induced neurological damages. In the present study, we examined the protective role of angiotensin IV (AngIV) in a rat model of embolic stroke induced by intracarotid injection of calibrated microspheres (50 microm). Internal carotid infusions of increasing doses of AngIV (0.01, 0.1 and 1 nmol/0.1 mL saline) dose dependently decreased mortality, neurological deficit and cerebral infarct size at 24 hours. With the highest dose of AngIV, mortality was reduced from 55 % in saline infused controls to 10 % (p=0.003), neurological deficit was reduced from 3.8 +/- 0.3 to 1.4 +/- 0.3 , (p<0.0001) and cerebral infarct size at 24 hours was decreased from 432 +/- 26 mm(3) to 185 +/- 19, (p=0.0001). The AT(4) antagonist divalinal-AngIV (10(-9) mol/0.1 mL), or pretreatment with L-NAME (10(-7) mol/0.1 mL), both completely abolished the protective effect of AngIV (1 nmol). The AT(2) antagonist PD123319 (10(-7) mol/0.1 mL) partially prevented the protective effect of AngIV on the neurological score. Sequential cerebral arteriographies revealed that AngIV induced a redistribution of blood flow to the ischemic areas within minutes. These results suggest that pharmacological doses of AngIV are protective against acute cerebral ischemia by triggering an AT(4)-mediated, NO-dependent intracerebral hemodynamic mechanism.
authors.affiliation: Physiologie et Pharmacologie Vasculaire et Rénale, Facultés de Médecine et de Pharmacie, Limoges, France.
authors.forename: S
authors.initials: S
authors.lastname: Faure
authors.forename: R
authors.initials: R
authors.lastname: Chapot
authors.forename: D
authors.initials: D
authors.lastname: Tallet
authors.forename: J
authors.initials: J
authors.lastname: Javellaud
authors.forename: J M
authors.initials: JM
authors.lastname: Achard
authors.forename: N
authors.initials: N
authors.lastname: Oudart
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000187:drug effects / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000098:blood supply; D002545:Brain Ischemia / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D002533:Cerebral Angiography; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020766:Intracranial Embolism / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology; D012039:Regional Blood Flow; D020521:Stroke / Q000188:drug therapy / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C090830:AT4 receptor; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-