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(Stroke. 2007;38:3007.)
© 2007 American Heart Association, Inc.

Original Contributions

Spontaneously Hypertensive Rats Are Highly Vulnerable to AMPA-Induced Brain Lesions

Clotilde Lecrux, PhD; Olivier Nicole, PhD; Laurent Chazalviel, BSc; Christelle Catone, PhD; Julien Chuquet, PhD; Eric T. MacKenzie, PhD Omar Touzani, PhD

From University of Caen, CNRS UMR 6185, Cyceron, Caen, France.

Correspondence to Dr Omar Touzani, Centre Cyceron, CNRS-UMR6185, Boulevard H. Becquerel, B.P.5229, F-14074 Caen, France. E-mail o.touzani{at}cyceron.fr

Background and Purpose— Whereas the effects of chronic arterial hypertension on the cerebral vasculature have been widely studied, its effects on brain tissue have been studied less so. Here we examined if spontaneously hypertensive rats (SHRs) or the normotensive control Wistar Kyoto rats (WKYs) made hypertensive by renal artery stenosis (R-WKYs) are vulnerable to an excitotoxic brain lesion provoked by an overactivation of glutamate receptors.

Methods— Lesion volumes were quantified by histology in WKYs and SHRs subjected to striatal administration of N-methyl-D-aspartate (NMDA) or -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). The expression of AMPA receptors subunits and calcium/calmodulin kinase-II was analyzed by real-time polymerase chain reaction and Western blot.

Results— NMDA (50 and 75 nmol) induced similar lesions in both SHRs (10±2 mm³ and 16±4 mm³, respectively) and WKYs (11±2 mm³ and 19±7 mm³, respectively). However, AMPA-induced (2.5 and 5 nmol) lesions were significantly greater in 14-week-old SHRs (14±3 mm³ and 20±5 mm³, respectively) than WKYs (4±2 mm³, P<0.05 and 7±4 mm³, P<0.001, respectively). Furthermore, normotensive 7-week-old SHRs also displayed an aggravated AMPA-induced lesion compared with age-matched WKYs (10±3 mm³ vs 6±3 mm³; P<0.05). Neither NMDA nor AMPA produced increased lesion volumes in R-WKYs (12±3 mm³ and 5±4 mm³, respectively) compared with WKYs. Striatal levels of AMPA receptors subunits, GluR1 and GluR2, were not different between SHRs and WKYs. However, SHRs displayed an increase in phosphorylated form of GluR1 at Ser-831 (P<0.05), as well as in calcium/calmodulin kinase-II (P<0.002). Selective inhibition of this kinase by KN-93 reduced AMPA-induced damage in SHRs (P<0.01 vs vehicle).

Conclusions— These findings show that an increase in phosphorylated GluR1, which increases AMPA receptor conductance, may be involved in the vulnerability of SHRs to AMPA.

Key Words: AMPA receptor • arterial hypertension • CaMKII • cerebral ischemia • excitotoxicity • GluR1