Reference - Detail
|Author||Inaba S, Iwai M, Tomono Y, Senba I, Furuno M, Kanno H, Okayama H, Mogi M, Higaki J, Horiuchi M.|
|Title||Exaggeration of focal cerebral ischemia in transgenic mice carrying human Renin and human angiotensinogen genes.|
BACKGROUND AND PURPOSE:We examined the possibility that activation of the human brain renin-angiotensin system is involved in enhancement of ischemic brain damage using chimeric transgenic mice with human renin (hRN) and human angiotensinogen (hANG) genes.
METHODS:Chimeric (hRN/hANG-Tg) mice were generated by mating of hRN and hANG transgenic mice. Permanent occlusion of the middle cerebral artery (MCA) by an intraluminal filament technique induced focal ischemic brain lesions.
RESULTS:hRN/hANG-Tg mice showed higher angiotensin II levels in the plasma and brain. The ischemic brain area at 24 hours after MCA occlusion was significantly enlarged in hRN/hANG-Tg mice with an enhanced neurological deficit compared to that in wild-type, hRN-Tg and hANG-Tg mice. The reduction of cerebral blood flow in the periphery region of the MCA territory after MCA occlusion was markedly exaggerated in hRN/hANG-Tg mice. Superoxide anion production in the brain and arteries was also increased significantly in hRN/hANG-Tg mice even before MCA occlusion and was further enhanced after MCA occlusion. Treatment with an AT(1) receptor blocker, valsartan (3.0 mg/kg per day), for 2 weeks significantly reduced the ischemic brain area and improved the neurological deficit after MCA occlusion in hRN/hANG-Tg mice, similar to those in wild-type, hRN-Tg, and hANG-Tg mice, with restoration of cerebral blood flow in the peripheral region and decreases in superoxide anion production and blood pressure.
CONCLUSIONS:These results indicate that activation of the human renin-angiotensin system exaggerates ischemic brain damage mainly through stimulation of the AT(1) receptor and marked reduction of cerebral blood flow and enhanced oxidative stress.
|MeSH||Angiotensin II / metabolism Angiotensin II Type 1 Receptor Blockers / pharmacology Angiotensin II Type 1 Receptor Blockers / therapeutic use Angiotensinogen / genetics* Animals Brain Chemistry / genetics Brain Chemistry / physiology Brain Ischemia / drug therapy Brain Ischemia / genetics* Brain Ischemia / pathology* Capillaries / pathology Cerebrovascular Circulation Humans Infarction, Middle Cerebral Artery / pathology Male Mice Mice, Transgenic Oxidative Stress / physiology Receptor, Angiotensin, Type 1 / biosynthesis Receptor, Angiotensin, Type 1 / genetics Receptor, Angiotensin, Type 2 / biosynthesis Receptor, Angiotensin, Type 2 / genetics Renin / genetics* Reverse Transcriptase Polymerase Chain Reaction Superoxides / metabolism Tetrazoles / pharmacology Valine / analogs & derivatives Valine / pharmacology Valsartan|
|WOS Category||CLINICAL NEUROLOGY PERIPHERAL VASCULAR DISEASE|