Severe Cerebral Blood Flow Reduction Inhibits Nitric Oxide Synthesis

Abstract

The purpose of this study was to investigate the relationship between cerebral blood flow (CBF) and nitric oxide (NO) synthesis using a rat model of transient forebrain ischemia of varying severity. Forebrain ischemia was induced for 30 min by occlusion of the bilateral common carotid arteries without hemorrhagic hypotension. The production of NO end-products (nitrite and nitrate) was measured by in vivo microdialysis, and CBF by the hydrogen clearance technique. Ischemia induced NO synthesis, although the increase in the quantity of NO end-products was not remarkable during the ischemic period but became prominent after reperfusion. Such increases were abolished by Nomega-nitro-L-arginine methyl ester (L-NAME), although 7-nitroindazole (7-NI) appeared to have only slight effects. The production of NO end-products during ischemia increased when the CBF during ischemia was less than 60 mL/100 g/min. In animals in which the CBF during ischemia was higher than 22.7 mL/100 g/min, the production of NO end-products increased gradually after the induction of ischemia and reached a peak during the reperfusion period, whereas in other animals in which the CBF during ischemia fell below 22.7 mL/100 g/min, the NO end-products decreased during ischemia and increased transiently after reperfusion. These results suggest that the increase in NO end-products is NO synthase (NOS)-dependent and that most of the increase is derived from endothelial NOS. It is also suggested that NO synthesis during ischemia is closely related to CBF, and that severe CBF reduction may inhibit NO synthesis.

Role of Nitric Oxide Synthases in Early Blood-Brain Barrier Disruption following Transient Focal Cerebral Ischemia

“…However, NO concentration is transiently increased by 50% for about 30 minutes if reperfusion occurs even when iNOS has not been induced [35], [36]. A previous study suggested that NO generation during early reperfusion was mostly derived from eNOS [36]. In the present study, eNOS-specific inhibitor showed a strong inhibitory effect on cerebral vasodilation during early reperfusion, whereas nNOS-specific and iNOS-specific inhibitors only showed inhibitory effect on cerebral dilation in certain branches of the MCA.…”

“…This enhanced and prolonged NO release can be entirely ascribed to the induced expression of iNOS in response to locally produced inflammatory cytokines following ischemia with or without reperfusion [33], [34]. However, NO concentration is transiently increased by 50% for about 30 minutes if reperfusion occurs even when iNOS has not been induced [35], [36]. A previous study suggested that NO generation during early reperfusion was mostly derived from eNOS [36].…”

Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances

“…Ischemia associated with occlusion of the bilateral common carotid arteries induced increases in NO end-products (NOx) during ischemia and prominently after reperfusion, and such increases were abolished by L-NAME but only slightly reduced by 7-NI; the increase in the quantity of NO end-products became prominent and was persistent after reperfusion in rats in which the cerebral blood flow during ischemia was in the range between 22.7 and 60 ml/100 g/min, whereas in animals in which the cerebral blood flow during ischemia fell below 22.7 ml/100 g/min, the end-products decreased during ischemia increased transiently after reperfusion. (Uetsuka et al, 2002). The increase in NO seems to be derived from eNOS, and NO synthesis during and after ischemia may be related to cerebral blood flow.…”

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

“…Thereafter, the brain tissue NO is reduced below detectable levels for up to 7 days (Malinski et al, 1993;Sugimura et al, 1998), indicating a long-lasting NO deficiency in the ischemic brain. If reperfusion occurs, NO concentration may transiently increase by 50% for about 30 minutes (Fassbender et al, 2000;Uetsuka et al, 2002). Concomitant with changes in NO levels, the activities of eNOS and nNOS increases within the first few minutes after MCAo, but decrease significantly thereafter (Kader et al, 1993).…”