Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury.
OBJECTIVE
Nitric oxide mediates endothelium-dependent vasodilation, modulates cerebral blood flow, and determines stroke outcome. Nitric oxide signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To study the role of sGC in stroke injury, we compared the outcome of cerebral ischemia and reperfusion in mice deficient in the alpha(1) subunit of sGC (sGCalpha(1)(-/-)) with that in wild-type mice.


METHODS
Blood pressure, cerebrovascular anatomy, and vasoreactivity of pressurized carotid arteries were compared in both mouse genotypes. Cerebral blood flow was measured before and during middle cerebral artery occlusion and reperfusion. We then assessed neurological deficit and infarct volume after 1 hour of occlusion and 23 hours of reperfusion and after 24 hours of occlusion.


RESULTS
Blood pressure and cerebrovascular anatomy were similar between genotypes. We found that vasodilation of carotid arteries in response to acetylcholine or sodium nitroprusside was diminished in sGCalpha(1)(-/-) compared with wild-type mice. Cerebral blood flow deficits did not differ between the genotypes during occlusion, but during reperfusion, cerebral blood flow was 45% less in sGCalpha(1)(-/-) mice. Infarct volumes and neurological deficits were similar after 24 hours of occlusion in both genotypes. After 1 hour of ischemia and 23 hours of reperfusion, infarct volumes were 2-fold larger and neurological deficits were worse in sGCalpha(1)(-/-) than in the wild-type mice.


CONCLUSIONS
sGCalpha(1) deficiency impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse neurological damage, suggesting that cGMP generated by sGCalpha(1)beta(1) is protective in ischemic stroke.
Atochin
Dmitriy N
DN
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Mass, USA. atochin@cvrc.mgh.harvard.edu
Yuzawa
Izumi
I
Li
Qian
Q
Rauwerdink
Kristen M
KM
Malhotra
Rajeev
R
Chang
Junlei
J
Brouckaert
Peter
P
Ayata
Cenk
C
Moskowitz
Michael A
MA
Bloch
Kenneth D
KD
Huang
Paul L
PL
Buys
Emmanuel S
ES
D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D002560:Cerebrovascular Circulation / Q000235:genetics; D005838:Genotype; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D015424:Reperfusion; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018709:Statistics, Nonparametric
D009569:Nitric Oxide; D006162:Guanylate Cyclase