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

Abstract

The role of nitric oxide synthases (NOSs) in early blood-brain barrier (BBB) disruption was determined using a new mouse model of transient focal cerebral ischemia. Ischemia was induced by ligating the middle cerebral artery (MCA) at its M2 segment and reperfusion was induced by releasing the ligation. The diameter alteration of the MCA, arterial anastomoses and collateral arteries were imaged and measured in real time. BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. The reperfusion produced an extensive vasodilation and a sustained hyperemia. Although expression of NOSs was not altered at 3 hours of reperfusion, L-NAME (a non-specific NOS inhibitor) abolished reperfusion-induced vasodilation/hyperemia and significantly reduced EB and Na-F extravasation. L-NIO (an endothelial NOS (eNOS) inhibitor) significantly attenuated cerebral vasodilation but not BBB disruption, whereas L-NPA and 7-NI (neuronal NOS (nNOS) inhibitors) significantly reduced BBB disruption but not cerebral vasodilation. In contrast, aminoguanidine (AG) (an inducible NOS (iNOS) inhibitor) had less effect on either cerebral vasodilation or BBB disruption. On the other hand, papaverine (PV) not only increased the vasodilation/hyperemia but also significantly reduced BBB disruption. Combined treatment with L-NAME and PV preserved the vasodilation/hyperemia and significantly reduced BBB disruption. Our findings suggest that nNOS may play a major role in early BBB disruption following transient focal cerebral ischemia via a hyperemia-independent mechanism.

Middle cerebral artery remodeling following transient brain ischemia is linked to early postischemic hyperemia: A target of uric acid treatment

“…However, we cannot exclude that hyperemia might be related to higher reductions of CBF in the core of the infarction during ischemia, since our laser Doppler CBF measurement was taken from a superficial cortical area. Previous studies have proposed that hyperemia is linked to an increase in NO production (12,13). In the present study we did not find changes in MCA NOS protein expression among groups.…”

Relaxin Peptide Hormones Are Protective During the Early Stages of Ischemic Stroke in Male Rats

“…If RXFP1 activation results in protection through eNOS signaling and increased blood flow, targeting this receptor may be less effective in tMCAO, where blood flow is restored. Furthermore, excessive NO production during ischemia/ reperfusion may result in hyperemia and blood-brain barrier breakdown (36). Although we have demonstrated relaxin-mediated protection through activation of eNOS, in healthy neural tissue neuronal NOS (nNOS) is also a principal synthase involved in NO production.…”

Early Recruitment of Cerebral Microcirculation by Neuronal Nitric Oxide Synthase Inhibition in a Juvenile Ischemic Rat Model

“…Dynamic connections occur during MCA occlusion, but disappear after spontaneous reperfusion [20] . Furthermore, transient [21,22] or sustained [23] hyperemia as described in the adult ischemic rat is [7] permits improved CBF in the great arteries at P14. Unexpectedly, and in contrast to data reported in the adult ischemic rat, 7-NI given before ischemia does not reduce BF during ischemia and does not alter reperfusion.…”