Angiotensin AT2 receptor stimulation increases survival in gerbils with abrupt unilateral carotid ligation.
Previous studies showed that angiotensin II (AII) infusion increased survival in gerbils subjected to abrupt unilateral carotid ligation. Recently, stimulation of the AII AT2 receptor, reportedly effectively extended the blood pressure (BP) range of cerebral blood flow (CBF) autoregulation. We evaluated the survival of gerbils treated with PD-123319, a ligand of AT2 receptors, to test the hypothesis that restoration of BF to ischemic cerebral tissue produced by AII is mediated through AT2 receptors. Abrupt unilateral carotid ligation was performed on 300 gerbils. In five experimental groups, animals received no drug pretreatment: (a) saline; (b)-(d) PD-123319 1.0, 3.0, and 10 mg/kg; and (e) losartan 10 mg/kg. In three additional experimental groups, animals were pretreated with enalaprilat: (f) saline; (g) PD-123319, 10 mg/kg, and (h) losartan, 10 mg/kg. Survival for 48 h was significantly improved by PD-123319 (10 mg/kg) (p < 0.05) and by losartan (10 mg/kg) (p < 0.05) as compared with animals injected with saline. Pretreatment with enalaprilat neutralized the protective effect of losartan. PD-123319 is an AT2 agonist and improved survival in this animal model of stroke. Losartan, an AT1 antagonist, also improved survival, possibly through renin release and AT2 stimulation by endogenous AII. This effect was neutralized by enalaprilat.
Fernandez
L A
LA
Department of Diagnostic Radiology, Yale Medical School, New Haven, Connecticut.
Caride
V J
VJ
Strömberg
C
C
Näveri
L
L
Wicke
J D
JD
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism*; D002339:Carotid Arteries; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015773:Enalaprilat / Q000494:pharmacology; D005849:Gerbillinae; D007093:Imidazoles / Q000494:pharmacology*; D008026:Ligation; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D011945:Receptors, Angiotensin / Q000819:agonists / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D016019:Survival Analysis; D013777:Tetrazoles / Q000494:pharmacology
D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C073402:PD 123319; D015773:Enalaprilat; D019808:Losartan