Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage.
We sought to determine whether expression of the inducible, calcium-independent isoform of nitric oxide synthase (iNOS) contributes to the tissue damage produced by focal cerebral ischemia. The middle cerebral artery was occluded in halothane-anesthetized spontaneously hypertensive rats. Twenty-four hours later rats received intraperitoneal injections of the iNOS inhibitor aminoguanidine (100 mg/kg twice per day; n = 10) or of aminoguanidine + L-arginine (300 mg/kg four times per day; n = 7), aminoguanidine + D-arginine (n = 7), arginine alone (n = 6), or vehicle (n = 9). Drugs were administered for 3 consecutive days. Infarct volume was determined by image analysis in thionin-stained brain sections 4 days after induction of ischemia. Administration of aminoguanidine reduced infarct volume by 33 +/- 4% (P < 0.05 from vehicle; analysis of variance and Tukey's test), a reduction that was antagonized by coadministration of L- but not D-arginine. Administration of L-arginine alone did not affect infarct size (P > 0.05 vs. vehicle). In separate rats (n = 10), aminoguanidine attenuated calcium-independent NOS activity in the infarct (P < 0.05 vs. vehicle) without affecting calcium-dependent activity (P > 0.05). Aminoguanidine did not affect resting cerebral blood flow or the cerebrovascular vasodilation elicited by hypercapnia, as determined by laser-Doppler flowmetry (n = 4). We conclude that aminoguanidine selectively inhibits iNOS activity in the area of infarction and reduces the volume of the infarct produced by middle cerebral artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Iadecola
C
C
Department of Neurology, University of Minnesota, Minneapolis 55455.
Zhang
F
F
Xu
X
X
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004790:Enzyme Induction; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism; D014664:Vasodilation / Q000187:drug effects
D001786:Blood Glucose; D006146:Guanidines; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C004479:pimagedine