Inhibition of nitric oxide synthesis increases focal ischemic infarction in rat.
We investigated whether inhibition of nitric oxide (NO) biosynthesis with N-omega-nitro-L-arginine (NNA), a competitive inhibitor of NO synthase (NOS), would modify the volume of the focal ischemic infarction produced by occlusion of the middle cerebral artery (MCA) in spontaneously hypertensive rats. NNA was infused for 1 h (2.4 mg/kg/h) immediately following occlusion of the MCA. NNA increased lesion volume 24 h later by 32% over controls (150.8 +/- 16.6 to 199.2 +/- 17.4 mm3; p less than 0.001, n = 6). This effect was antagonized by co-infusion of L- but not D-arginine. The antihypertensive rilmenidine (0.75 mg/kg) reduced the lesion by 27% (p less than 0.05, n = 4). Changes in lesion size were confined to the penumbra. NNA increased arterial pressure (AP) (118 +/- 8.9 to 149 +/- 16.0 mm Hg; p less than 0.01, n = 3) but did not change regional CBF. However, elevation of AP did not change the lesion volume or distribution. We conclude that inhibition of the constitutive form of NOS in vivo increases the volume of focal ischemic infarction as a consequence of reduced NO biosynthesis. The absence of NO availability may extend lesion formation by inhibition of reactive hyperemia, platelet disaggregation, and/or release of neuroprotective neuromodulators in the penumbra, which may counteract and override any of its neurotoxic actions.
Yamamoto
S
S
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021.
Golanov
E V
EV
Berger
S B
SB
Reis
D J
DJ
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002544:Cerebral Infarction / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D010080:Oxazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D000077769:Rilmenidine
D000959:Antihypertensive Agents; D010080:Oxazoles; D010656:Phenylephrine; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D000077769:Rilmenidine