Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning.

Abstract

Neuroprotection against cerebral ischemia can be realized if the brain is preconditioned by previous exposure to a brief period of sublethal ischemia. The present study was undertaken to test the hypothesis that nitric oxide (NO) produced from the neuronal isoform of NO synthase (NOS) serves as a necessary signal for establishing an ischemia-tolerant state in brain. A newborn rat model of hypoxic preconditioning was used, wherein exposure to sublethal hypoxia (8% oxygen) for 3 hours renders postnatal day (PND) 6 animals completely resistant to a cerebral hypoxic-ischemic insult imposed 24 hours later. Postnatal day 6 animals were treated 0.5 hour before preconditioning hypoxia with the nonselective NOS inhibitor L-nitroarginine (2 mg/kg intraperitoneally). This treatment, which resulted in a 67 to 81% inhibition of calcium-dependent constitutive NOS activity 0.5 to 3.5 hours after its administration, completely blocked preconditioning-induced protection. However, administration of the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg intraperitoneally) before preconditioning hypoxia, which decreased constitutive brain NOS activity by 58 to 81%, was without effect on preconditioning-induced cerebroprotection, as was pretreatment with the inducible NOS inhibitor aminoguanidine (400 mg/kg intraperitoneally). The protective effects of preconditioning were also not blocked by treating animals with competitive [3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate; 5 mg/kg intraperitoneally] or noncompetitive (MK-801; 1 mg/kg intraperitoneally) N-methyl-D-aspartate receptor antagonists prior to preconditioning hypoxia. These findings indicate that NO production and activity are critical to the induction of ischemic tolerance in this model. However, the results argue against the involvement of the neuronal NOS isoform, activated secondary to a hypoxia-induced stimulation of N-methyl-D-aspartate receptors, and against the involvement of the inducible NOS isoform, but rather suggest that NO produced by the endothelial NOS isoform is required to mediate this profound protective effect.

• Authors: J M Gidday, A R Shah, R G Maceren, Q Wang, D A Pelligrino, D M Holtzman, T S Park
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 19 Issue 3 Pg. 331-40 (Mar 1999) ISSN: 0271-678X [Print] United States
• PMID: 10078885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Guanidines
• Indazoles
• Piperazines
• Receptors, N-Methyl-D-Aspartate
• Nitroarginine
• Nitric Oxide
• Dizocilpine Maleate
• 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos2 protein, rat
• Nos3 protein, rat
• Oxygen
• pimagedine
• Calcium
• 7-nitroindazole

Topics

• Animals
• Animals, Newborn
• Brain Ischemia (prevention & control)
• Calcium (pharmacology)
• Dizocilpine Maleate (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Guanidines (pharmacology)
• Hypoxia (physiopathology)
• Indazoles (pharmacology)
• Nitric Oxide (physiology)
• Nitric Oxide Synthase (antagonists & inhibitors, physiology)
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nitroarginine (pharmacology)
• Oxygen (administration & dosage)
• Piperazines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, physiology)