Effects in cats of inhibition of nitric oxide synthesis on cerebral vasodilation and endothelium-derived relaxing factor from acetylcholine.

Wei, Enoch P.; Kukreja, Rakesh C.; Kontos, Hermes A.

doi:10.1161/01.str.23.11.1623

Cited by 45 publications

(11 citation statements)

References 21 publications

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“…We found that the vasodilation produced by neocortical application of ACh, a response mediated by local release of endothelial nitric oxide (Faraci, 1992;Wei et al, 1992), is reduced in these mice. The effect cannot be attributed to a nonspecific loss in vascular reactivity or to an impairment of the response of vascular smooth muscles to nitric oxide, because the vasodilation produced by the nitric oxide donor SNAP was not affected.…”

Section: Discussionmentioning

confidence: 78%

Increased Susceptibility to Ischemic Brain Damage in Transgenic Mice Overexpressing the Amyloid Precursor Protein

et al. 1997

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We studied the role of the amyloid precursor protein (APP) in ischemic brain damage using transgenic mice overexpressing APP. The middle cerebral artery (MCA) was occluded in FVB/N mice expressing APP 695 .SWE (Swedish mutation) and in nontransgenic littermates. Infarct volume (cubic millimeters) was assessed 24 hr later in thionin-stained brain sections. The infarct produced by MCA occlusion was enlarged in the transgenics (ϩ32 Ϯ 6%; n ϭ 12; p Ͻ 0.05; t test). Measurement of APP by ELISA revealed that, although relatively high levels of A␤ were present in the brain of the transgenics (A␤ 1-40 ϭ 80 Ϯ 19 pmol/g; n ϭ 6), there were no differences between ischemic and nonischemic hemispheres ( p Ͼ 0.05). The reduction in cerebral blood flow produced by MCA occlusion at the periphery of the ischemic territory was more pronounced in APP transgenics (Ϫ42 Ϯ 8%; n ϭ 9) than in controls (Ϫ20 Ϯ 8%; n ϭ 9). Furthermore, the vasodilatation produced by neocortical application of the endothelium-dependent vasodilator acetylcholine (10 M) was reduced by 82 Ϯ 5% (n ϭ 8; p Ͻ 0.05) in APP transgenics. The data demonstrate that APP overexpression increases the susceptibility of the brain to ischemic injury. The effect is likely to involve the A␤-induced disturbance in endothelium-dependent vascular reactivity that leads to more severe ischemia in regions at risk for infarction. The cerebral vascular actions of peptides deriving from APP metabolism may play a role in the pathogenic effects of APP. Key words: middle cerebral artery; Alzheimer's disease; cerebral ischemia; stroke; cerebral blood flow; transgenic miceThere is substantial evidence that the amyloid precursor protein (APP), a constitutively expressed transmembrane glycoprotein, is involved in the pathogenesis of Alzheimer's dementia (Price and Sisodia, 1994;Selkoe et al., 1996;Mattson et al., 1997). APP is present in different isoforms derived from a single gene by alternative splicing (Lendon et al., 1997). A 39 -42 amino acid fragment of APP, A␤, is present in amyloid plaques in the brain of patients with Alzheimer's disease and Down's syndrome and in normal brain aging (Lendon et al., 1997). Both in vitro and in vivo evidence suggest that A␤ is cytotoxic, an effect that may depend on the state of aggregation of A␤ (Mattson et al., 1993a). The mechanisms of the neurotoxicity of A␤ are thought to include perturbation of ionic homeostasis and free radical production (Mattson et al., 1993a;Fraser et al., 1997).It has been proposed that APP and A␤ may also participate in ischemic brain damage. Although APP expression is increased in the postischemic brain (Abe et al., 1991a,b;Stephenson et al., 1992;Wakita et al., 1992;Kalaria et al., 1993;Banati et al., 1995), cerebral ischemia may facilitate cleavage of APP into the toxic A␤ fragment (Saido et al., 1994;Yokota et al., 1996). These observations raise the possibility that ischemia leads to accumulation of A␤, which, in turn, could contribute to ischemic brain damage. On the other hand, there is also evidence that APP may ...

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Section: Discussionmentioning

confidence: 78%

Increased Susceptibility to Ischemic Brain Damage in Transgenic Mice Overexpressing the Amyloid Precursor Protein

et al. 1997

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“…Vessel diameters were measured 2-4 min following the topical application for each concentration of ACh. Under normal physiological conditions, ACh is known to dilate cerebral vessels via generation of an endotheliumderived relaxing factor of the NO type (Furchgott, 1983;Kontos et al, 1988;Wei et al, 1992). However, this normal vasodilator response caused by ACh is either reduced or converted to vasoconstriction following experimental TBI.…”

Section: Hypercapniamentioning

confidence: 99%

The Long-Term Microvascular and Behavioral Consequences of Experimental Traumatic Brain Injury after Hypothermic Intervention

Wei

Hamm

Baranova

et al. 2009

Journal of Neurotrauma

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Traumatic brain injury (TBI) has been demonstrated to induce cerebral vascular dysfunction that is reflected in altered responses to various vasodilators. While previous reports have focused primarily on the short-term vascular alterations, few have examined these vascular changes for more than 7 days, or have attempted to correlate these alterations with any persisting behavioral changes or potential therapeutic modulation. Accordingly, we evaluated the long-term microvascular and behavioral consequences of experimental TBI and their therapeutic modulation via hypothermia. In this study, one group was injured with no treatment, another group was injured and 1 h later was treated with 120 min of hypothermia followed by slow rewarming, and a third group was non-injured. Animals equipped with cranial windows for visualization of the pial microvasculature were challenged with various vasodilators, including acetylcholine, hypercapnia, adenosine, pinacidil, and sodium nitroprusside, at either 1 or 3 weeks post-TBI. In addition, all animals were tested for vestibulomotor tasks at 1 week post-TBI, and animals surviving for 3 weeks post-TBI were tested in a Morris water maze (MWM). The results of this investigation demonstrated that TBI resulted in long-term vascular dysfunction in terms of altered vascular reactivity to various vasodilators, which was significantly improved with the use of a delayed 120-min hypothermic treatment. In contrast, data from the MWM task indicated that injured animals revealed persistent deficits in the spatial memory test performance, with hypothermia exerting no protective effects. Collectively, these data illustrate that TBI can evoke long-standing brain vascular and spatial memory dysfunction that manifest different responses to hypothermic intervention. These findings further illustrate the complexity of TBI and highlight the fact that the chosen hypothermic intervention may not necessarily exert a global protective response.

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“…There is a precedent for the latter suggestion since indomethacin blocks phospholipase at concentrations that overlap with those on the concentrationinhibition curve for cyclooxygenase. 54 The data showing inhibition of L-NMMA's effects by either cyclooxygenase inhibitors or SOD were not replicated in a study of cat vessels, 52 but in the latter study there was no attempt made to prevent the action of L-NMMA. Instead, SOD was used in an attempt to reverse the effect of L-NMMA after it had br;en present for over an hour.…”

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confidence: 99%

Endothelium-derived relaxing factor in brain blood vessels is not nitric oxide.

Rosenblum

1992

Stroke

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Background: The endothelium-derived relaxing factor that mediates the actions of acetylcholine is now most frequently identified as nitric oxide. Nitric oxide is believed to have numerous important regulating actions in neurons, blood vessels, and several other biological systems.Summary of Review: The literature concerning tissue other than cerebral blood vessels supports the conclusion that the endothelium-derived relaxing factor for acetylcholine is either nitric oxide or a compound formed from and containing nitric oxide (for example, a nitrosothiol). However, papers can be found indicating that this endothelium-derived mediator is not nitric oxide. In brain blood vessels the evidence is strongly against the conclusion that nitric oxide is the endothelium-derived mediator for acetylcholine. If this mediator is formed from nitric oxide, either in brain vessels or in other vessels, no data are available delineating how this synthesis is regulated or whether and where nitric oxide leaves the nitroso compound to initiate dilation. Indeed, cerebrovascular data now cast doubt on the commonly held belief that nitrosovasodilators regulate vascular tone by giving off nitric oxide to vascular smooth muscle.Conclusions: In brain blood vessels the chemical identity of the endothelium-derived relaxing factor mediating the action of acetylcholine is unknown, but this relaxing factor does not appear to be nitric oxide. If the mediator contains nitric oxide, as is probably the case, the means by which it activates vascular guanylate cyclase and/or produces dilation is unknown. Since this relaxing factor inhibits platelet adhesion/aggregation in cerebral vessels as well as relaxing these vessels, the chemical identification of this relaxing factor and the elucidation of its mode of action are extremely important to our understanding and control of cerebrovascular phenomena in health and disease. (Stroke 1992;23:1527-1532)

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Effects in cats of inhibition of nitric oxide synthesis on cerebral vasodilation and endothelium-derived relaxing factor from acetylcholine.

Cited by 45 publications

References 21 publications

Increased Susceptibility to Ischemic Brain Damage in Transgenic Mice Overexpressing the Amyloid Precursor Protein

Increased Susceptibility to Ischemic Brain Damage in Transgenic Mice Overexpressing the Amyloid Precursor Protein

The Long-Term Microvascular and Behavioral Consequences of Experimental Traumatic Brain Injury after Hypothermic Intervention

Endothelium-derived relaxing factor in brain blood vessels is not nitric oxide.

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