Nitric Oxide Donors Increase Blood Flow and Reduce Brain Damage in Focal Ischemia: Evidence That Nitric Oxide is Beneficial in the Early Stages of Cerebral Ischemia

Abstract

Summary: We studied whether administration of nitric oxide (NO) donors reduces the ischemic damage resulting from middle cerebral artery (MCA) occlusion in sponta neously hypertensive rats (SHRs). In halothane anesthetized and ventilated SHRs, the MCA was oc cluded. CBF was monitored using a laser-Doppler flow meter. Three to five minutes after MCA occlusion, the NO donors sodium nitroprusside (SNP; 3 mg/kg/h) or 3-morpholino-sydnonimine (SIN 1; 1.5-6 mg/kg/h) were administered into the carotid artery for 60 min. As a con trol, the effect of papaverine (3.6 mg/kg/h), a vasodilator that acts independently of NO, was also studied. The hypotension evoked by these agents was counteracted by intravenous infusion of phenylephrine. At the end of the infusion, rats were allowed to recover. Stroke size was determined 24 h later in thionin-stained sections. In sham occluded rats, SNP (n = 5), SIN 1 (n = 5), and papav erine (n = 5) produced comparable increases in CBF (p > 0.05 from vehicle). After MCA occlusion, SNP (n = 5) and SIN 1 (n = 5), but not papaverine (n = 5), enhanced Nitric oxide (NO) is a ubiquitous free radical gas involved in a wide variety of biological processes (Moncada, 1992). In the systemic circulation, NO, produced in endothelial cells, regulates vascular re sistance and platelet aggregation (Moncada, 1992). In the immune system, NO is responsible for the 217the recovery of CBF (p < 0.05 from vehicle) and reduced the size of the infarct by 28 ± 12 and 32 ± 7%, respec tively (mean ± SD; p < 0.05 from vehicle). To determine whether NO donors could act by inhibiting platelet aggre gation, we studied the effect of SNP on collagen-induced platelet aggregation. Intracarotid administration of SNP (3 mg/kg/h for 60 min) did not affect platelet aggregation to collagen, suggesting that the protective effect of NO donors was not due to inhibition of platelet function. We conclude that NO donors increase CBF to the ischemic territory and reduce the tissue damage resulting from fo cal ischemia. The protective effect may result from an increase in CBF to the ischemic territory, probably the ischemic penumbra. These findings suggest that NO do nors may represent a new therapeutic strategy for the management of acute stroke.

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

“…Since the discovery that nitric oxide (NO), an endothelium-derived relaxing factor 22 , has 1000 times higher affinity for hemoglobin than oxygen 52 , neurosurgeons and neuroscientists have been interested in its role in cerebral vasospasm after SAH 2,8,16,44,45,55,[64][65][66]70,87,90,92,94,95,103 . NO influence on blood flow 11,15,99,106,113 , disappearance of neuronal nitric oxide synthase (nNOS) immunoreactivity from the arteries in spasm 75 , endothelial nitric oxide synthase (eNOS) dysfunction in cerebral vessels after SAH 37 , decreased levels of nitrite in the cerebrospinal fluid (CSF) during vasospasm development 40,70,76 , as well NO affinity for the heme moiety 52 together, strongly suggest that decreased availability of NO in the cerebral arterial wall after SAH is responsible for delayed cerebral vasospasm 70 . Recent research has significantly advanced our understanding of the NO-related pathophysiologic changes in the cerebral arteries leading to vasospasm and introduced new possibilities for NO-based therapy for vasospasm 23,76,98 .…”

Cilostazol, a Phosphodiesterase Inhibitor, Attenuates Photothrombotic Focal Ischemic Brain Injury in Hypertensive Rats

“…Briefly, neuronal and inducible NOS play roles in nerve degeneration, while endothelial NOS plays a role in maintaining CBF and preventing neuronal injury in ischemic brain (Samdani et al, 1997). NO donors such as L-arginine increased CBF and reduced brain damage in mechanical MCA occlusion models (Morikawa et al, 1994;Zhang et al, 1994). Recently, cilostazol has increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in the ischemic brain after MCA occlusion in rats (Nonaka et al, 2009).…”

S-Nitrosoglutathione Reduces Inflammation and Protects Brain against Focal Cerebral Ischemia in a Rat Model of Experimental Stroke

“…In fact, eNOS-deficient transgenic mice show larger infarct volumes compared with controls after MCAO (Huang et al, 1996). At an early time-point of ischemic insult, NO protects the brain by increasing CBF (Zhang and Iadecola, 1993;Zhang et al, 1994) and prevents apoptosis partly by inhibiting active caspases via S-nitrosylation (Mannick et al, 1999) and by inhibiting p50 subunit binding of NF-kB to DNA via S-nitrosylation (Marshall and Stamler, 2001). In contrast to eNOS, the activities of neuronal NO synthase (nNOS) and inducible NO synthase (iNOS) are broadly deleterious and their inhibition as well as gene deficiencies are neuroprotective in stroke (Huang et al, 1994;Zhao et al, 2000).…”