Cerebral ischemia enhances vascular angiotensin AT1 receptor-mediated contraction in rats.
OBJECTIVE
The aim of the study was to examine how focal cerebral ischemia affects the expression and function of vascular angiotensin II receptors.


METHODS
We used an intraluminal filament occlusion technique to occlude the right middle cerebral artery (MCA) of the rat. Myographs were used for functional studies of the MCA and real-time polymerase chain reaction, for determination of relative mRNA levels.


RESULTS
The contractile responses to angiotensin II were stronger in the right occluded MCA compared with the left MCA and the MCA from sham-operated rats 48 hours after MCA occlusion (P<0.05). The angiotensin II type 1 (AT1) receptor antagonists candesartan and losartan abolished the enhanced responses to angiotensin II (P<0.05), whereas the AT2 receptor antagonist PD123319 had no effect. The amount of AT1 receptor mRNA was lower in the occluded MCAs compared with nonoccluded MCAs 48 hours after occlusion (P<0.05), whereas the mRNA levels of angiotensin converting enzyme (ACE) were higher in the occluded arteries. The mRNA levels of the AT2 receptor and nuclear factor-kappaB were unchanged.


CONCLUSIONS
Focal cerebral ischemia in the rat upregulated the contractile responses to angiotensin II in the ipsilateral MCA, and this contraction was mediated by AT1 receptors. Real-time polymerase chain reaction revealed decreased AT1 receptor mRNA levels in the occluded MCA, whereas the amount of ACE mRNA was increased, suggesting locally enhanced angiotensin II production. These results support a role for AT1 receptors in cerebral ischemia, and we think that AT1 receptors might be a future therapeutic target in ischemic stroke.
Division of Experimental Vascular Research, Lund University, BMC A13, Sölvegatan 17, 221 84 Lund, Sweden. Emelie.Stenman@med.lu.se
Emelie
E
Stenman
Lars
L
Edvinsson
D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D046508:Culture Techniques; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000503:physiopathology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D019808:Losartan; C081643:candesartan