Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion.
OBJECTIVE
The present studies examined the hypothesis that the distribution of cerebral injury after a focal ischemic insult is associated with the regional distribution of nitric oxide synthase (NOS) activity.


METHODS
Based on previous studies that certain anatomically well-defined areas are prone to become either core or penumbra after middle cerebral artery occlusion (MCAO), we measured NOS activity in these areas from the right and left hemispheres in a spontaneously hypertensive rat filament model. Four groups were studied: (1) controls (immediate decapitation); (2) 1.5 hours of MCAO with no reperfusion (R0); (3) 1.5 hours of MCAO with 0.5 hour of reperfusion (R0.5); and (4) 1.5 hours of MCAO with 24 hours of reperfusion (R24). Three groups of corresponding isoflurane sham controls were also included: 1.5 (S1.5) or 2 (S2.0) hours of anesthesia and 1.5 hours of anesthesia+24 hours of observation (S24).


RESULTS
Control core NOS activity for combined right and left hemispheres was 129% greater than penumbral NOS activity (P<0.05). Combined core NOS activity was also greater (P<0.05) in the three sham groups: 208%, 122%, and 161%, respectively. In the three MCAO groups, ischemic and nonischemic core NOS remained higher than penumbral regions (P<0.05). However, NOS activity was lower in the ischemic than in the nonischemic core in all three groups: R0 (29% lower), R0.5 (48%), and R24 (86%) (P<0.05). Addition of cofactors (10 micromol/L tetrahydrobiopterin, 3 micromol/L flavin adenine dinucleotide, and 3 micromol/L flavin mononucleotide) increased NOS activity in all groups and lessened the decrease in ischemic core and penumbral NOS.


CONCLUSIONS
Greater NOS activity in core regions could explain in part the increased vulnerability of that region to ischemia and could theoretically contribute to the progression of the infarct over time. The data also suggest that NOS activity during ischemia and reperfusion could be influenced by the availability of cofactors.
Ashwal
S
S
Department of Pediatrics, Loma Linda University School of Medicine, Calif 92354, USA. Stephen_Ashwal@ccmail.llumc.edu
Tone
B
B
Tian
H R
HR
Cole
D J
DJ
Pearce
W J
WJ
D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001157:Arterial Occlusive Diseases / Q000201:enzymology; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D002536:Cerebral Arteries / Q000201:enzymology*; D006224:Cricetinae; D005486:Flavin Mononucleotide / Q000008:administration & dosage / Q000494:pharmacology; D005182:Flavin-Adenine Dinucleotide / Q000008:administration & dosage / Q000494:pharmacology; D007530:Isoflurane / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D011918:Rats, Inbred SHR; D015424:Reperfusion; D015427:Reperfusion Injury / Q000201:enzymology*; D013997:Time Factors
D018685:Anesthetics, Inhalation; D000975:Antioxidants; D005182:Flavin-Adenine Dinucleotide; D001708:Biopterins; D005486:Flavin Mononucleotide; D007530:Isoflurane; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C003402:sapropterin