Spontaneously hypertensive rats are highly vulnerable to AMPA-induced brain lesions.
OBJECTIVE
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 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). The expression of AMPA receptors subunits and calcium/calmodulin kinase-II alpha 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 mm(3) and 16+/-4 mm(3), respectively) and WKYs (11+/-2 mm(3) and 19+/-7 mm(3), respectively). However, AMPA-induced (2.5 and 5 nmol) lesions were significantly greater in 14-week-old SHRs (14+/-3 mm(3) and 20+/-5 mm(3), respectively) than WKYs (4+/-2 mm(3), P<0.05 and 7+/-4 mm(3), P<0.001, respectively). Furthermore, normotensive 7-week-old SHRs also displayed an aggravated AMPA-induced lesion compared with age-matched WKYs (10+/-3 mm(3) vs 6+/-3 mm(3); P<0.05). Neither NMDA nor AMPA produced increased lesion volumes in R-WKYs (12+/-3 mm(3) and 5+/-4 mm(3), 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 alpha (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.
Lecrux
Clotilde
C
University of Caen, CNRS UMR 6185, Cyceron, Caen, France.
Nicole
Olivier
O
Chazalviel
Laurent
L
Catone
Christelle
C
Chuquet
Julien
J
MacKenzie
Eric T
ET
Touzani
Omar
O
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001925:Brain Damage, Chronic / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D006973:Hypertension / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018698:Glutamic Acid; D009498:Neurotoxins; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid