Nitric oxide synthase in cerebral ischemia

Abstract

The results of our continuing studies on the role of nitric oxide (NO) in cellular mechanisms of ischemic brain damage as well as related reports from other laboratories are summarized in this paper. Repetitive ip administration of NG-nitro-L-arginine (L-NNA), a NO synthase (NOS) inhibitor, protected against neuronal necrosis in the gerbil hippocampal CA1 field after transient forebrain ischemia with a bell-shaped response curve, the optimal dose being 3 mg/kg. Repeated ip administration of L-NNA also mitigated rat brain edema or infarction following permanent and transient middle cerebral artery (MCA) occlusion with a U-shaped response. The significantly ameliorative dose-range and optimal dose were 0.01-1 mg/kg and 0.03 mg/kg, respectively. Studies using a NO-sensitive microelectrode revealed that NO concentration in the affected hemisphere was remarkably increased by 15-45 min and subsequently by 1.5-4 h after MCA occlusion. Restoration of blood flow after 2 h-MCA occlusion resulted in enhanced NO production by 1-2 h after reperfusion. Administration of L-NNA (1 mg/kg, ip) diminished the increments in NO production during ischemia and reperfusion, leading to a remarkable reduction in infarct volume. In brain microvessels obtained from the affected hemisphere, Ca(2+)-dependent constitutive NOS (cNOS) was activated significantly at 15 min, and Ca(2+)-independent inducible NOS (iNOS) was activated invariably at 4 h and 24 h after MCA occlusion. Two hour reperfusion following 2 h-MCA occlusion caused more than fivefold increases in cNOS activity with no apparent alterations in iNOS activity. Thus, we report here based on available evidence that there is good reason to think that NOS activation in brain microvessels may play a role in the cellular mechanisms underlying ischemic brain injury.

Reduction of CuZn-Superoxide Dismutase Activity Exacerbates Neuronal Cell Injury and Edema Formation after Transient Focal Cerebral Ischemia

“…The latter pathway more likely explains the phenomenon in the mutants, because endothelial cells are an abundant source of nitric oxide from their constitutive nitric oxide synthase. Consistent with this inference is recent evidence suggesting that the constitutive endothelial nitric oxide synthase is activated after focal cerebral ischemia and reperfusion (Nagafuji et al, 1995).…”

Transient Focal Ischemia Increases Endothelial Nitric Oxide Synthase in Cerebral Blood Vessels

“…8,10 Vascular eNOS protein expression is believed to increase very rapidly after focal ischemia. 10 However, except for 2 studies using assays without NOS isoenzyme selectivity, 16,17 this concept is based on a single study using eNOS-specific immunostaining in a permanent focal ischemia model. 20 In this study, eNOS expression was higher in the ischemic compared with the nonischemic hemisphere.…”

“…13,14 Cerebral ischemia itself affects microvascular NOS activity and expression in several species. 5,8,[15][16][17][18][19][20][21][22] So far, only 1 study has characterized vascular eNOS isoenzyme expression after permanent focal ischemia. 20 A second confirmatory and better-quantifiable method such as eNOS immunoblotting was not performed.…”

4-Hydroxy-2-nonenal antimicrobial toxicity is neutralized by an intracellular pathogen

“…The freely diffusible and highly reactive diatomic gas nitric oxide (NO) is produced during infection (Iyengar, Stuehr and Marletta, 1987;Stuehr and Marletta, 1985) and has a direct role in preventing bacterial growth (Nathan and Hibbs, 1991). However, due to the conservation of its reactive targets, elevated levels of NO also exert pathological effects during both sterile inflammation and acute infections (Nagafuji et al, 1995;Galley and Webster, 1998). 4-HNE is membrane diffusible, highly reactive, and contributes to disease pathology due to its cytotoxic activity toward eukaryotic cells.…”