Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage

Am J Physiol. 1995 Jan;268(1 Pt 2):R286-92. doi: 10.1152/ajpregu.1995.268.1.R286.

Abstract

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)

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / biosynthesis*
  • Analysis of Variance
  • Animals
  • Arginine / pharmacology*
  • Blood Glucose / drug effects
  • Blood Pressure / drug effects
  • Brain / drug effects
  • Brain / enzymology*
  • Brain / pathology
  • Brain Ischemia / pathology
  • Brain Ischemia / prevention & control*
  • Cerebral Infarction / pathology
  • Cerebral Infarction / prevention & control*
  • Cerebrovascular Circulation / drug effects
  • Enzyme Induction
  • Guanidines / pharmacology*
  • Male
  • Nitric Oxide Synthase
  • Rats
  • Rats, Inbred SHR
  • Stereoisomerism
  • Vasodilation / drug effects

Substances

  • Blood Glucose
  • Guanidines
  • Arginine
  • Nitric Oxide Synthase
  • Amino Acid Oxidoreductases
  • pimagedine