Selective Depression of Endothelium-Dependent Dilations During Cerebral Ischemia

Rosenblum, William I.; Wormley, Brandon

doi:10.1161/01.str.26.10.1877

Cited by 16 publications

(11 citation statements)

References 17 publications

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“…That no additional increase in leukocyte adherence occurred during the early postischemic reperfusion period after NOS inhibition by L-NA suggests that asphyxia-reperfusion resulted in a depletion of endogenous basal levels of NO. As found in other tissues, recent studies in brain 37 document an attenuation or absence of NO-dependent vasoreactivity during the initial hours after ischemia, even though reactivity to NO donors remains intact, indicating that endothelial NOS function is impaired after ischemia and/or that NO is efficiently scavenged once it is produced. The robust increase in oxygen free radical formation occurring coincident with postischemic reperfusion 38 is consistent with the latter possibility but does not explain how NO donors retain their vasoactivity after ischemia.…”

Section: Discussionmentioning

confidence: 61%

Modulation of Basal and Postischemic Leukocyte-Endothelial Adherence by Nitric Oxide

Gidday

Park

Shah

et al. 1998

Stroke

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Background and Purpose-Recent studies indicate that leukocytes are important contributors to secondary vascular and parenchymal injury after cerebral ischemia. The present study was undertaken to define nitric oxide (NO)Ϫbased mechanisms that regulate leukocyte-endothelial interactions in the cerebral vasculature, how these mechanisms are affected by cerebral ischemia, and whether NO-based therapies can affect postischemic leukocyte dynamics. Methods-Leukocyte adherence to pial venules of anesthetized newborn piglets was quantified by in situ fluorescence videomicroscopy through closed cranial windows during basal conditions and during reperfusion after 9 minutes of asphyxia. Nitric oxide synthase (NOS) was inhibited by local window superfusion of L-nitroarginine; superfusion of sodium nitroprusside was used to donate NO. Results-Local inhibition of NOS under resting conditions increased leukocyte-endothelial adherence 2.2-fold and 3.9-fold over baseline values after 1 hour and 2 hours, respectively; this response was completely blocked by cosuperfusion with L-arginine. Cosuperfusion of superoxide dismutase reversed L-nitroarginineϪinduced leukocyte adherence by 89% and 63% at these respective time points. The extent of acute leukocyte adherence elicited by NOS inhibition was similar in magnitude to that observed during the initial 2 hours of reperfusion after asphyxia. Leukocyte adherence was not additionally increased in asphyxic animals treated with L-nitroarginine. Sodium nitroprusside robustly inhibited asphyxia-induced leukocyte adherence back to control levels. Conclusions-NO exerts a tonic antiadherent effect in the cerebral microcirculation by inactivation of adherencepromoting superoxide radical formation. Cerebral ischemia is associated with an inhibition of NOS or lower levels of NO, which results in leukocyte-endothelial adherence that can be prevented by NO donors. The latter may be useful therapeutically to prevent the purported vascular and parenchymal dysfunction and injury caused by activated leukocytes in ischemic brain.

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Section: Discussionmentioning

confidence: 61%

Modulation of Basal and Postischemic Leukocyte-Endothelial Adherence by Nitric Oxide

Gidday

Park

Shah

et al. 1998

Stroke

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“…Likewise, the expression of some genes is induced (e.g., adhesion molecules, cytokines), whereas expression of others (e.g., constitutive nitric oxide synthase, thrombomodulin) is suppressed in hypoxic endothelial cells. In arterioles, the endothelial cell dysfunction is manifested as an impaired endothelium-dependent, NO-mediated relaxation of smooth muscle to all receptor-dependent vasodilators, such as acetylcholine (36).…”

mentioning

confidence: 99%

In vivo reactive oxygen species production induced by ischemia in muscle arterioles of mice: involvement of xanthine oxidase and mitochondria

Baudry

Laemmel²,

Vicaut³

2008

American Journal of Physiology-Heart and Circulatory Physiology

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Reactive oxygen species (ROS) participate in tissue injury after ischemia-reperfusion. Their implication in leukocyte adherence and increase in permeability at the venular side of the microcirculation have been reported, but very little is known about ROS production in arterioles. The objective of this work was to evaluate, in the arteriole wall in vivo, the temporal changes in superoxide anion production during ischemia and reperfusion and to identify the source of this production. Mouse cremaster muscle was exposed to 1 h of ischemia followed by 30 min of reperfusion, and superoxide anion production was assessed by a fluorescent probe, i.e., intracellular dihydroethidium oxidation. During ischemia, we found a significant increase in dihydroethidium oxidation; however, we observed no additional increase in fluorescence during the subsequent reperfusion. This phenomenon was significantly inhibited by pretreatment with superoxide dismutase. Allopurinol (xanthine oxidase inhibitor) or stigmatellin [Q(o)-site (oriented toward the intermembrane space) inhibitor of mitochondrial complex III] or simultaneous administration of these two inhibitors significantly reduced superoxide production during ischemia to 80%, 88%, and 72%, respectively, of that measured in the untreated ischemia-reperfusion group. By contrast, no significant inhibition was found when NADPH oxidase was inhibited by apocynin or when mitochondrial complex I or complex II was inhibited by rotenone or thenoyltrifluoroacetone. A significant increase in ROS was found with antimycin A [Q(i)-site (located in the inner membrane and facing the mitochondrial matrix) inhibitor of mitochondrial complex III]. We conclude that a significant increase in ROS production occurs during ischemia in the arteriolar wall. This increased production involves both a cytoplasmic source (i.e., xanthine oxidase) and the mitochondrial complex III at the Q(o) site.

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“…Depressed postischemic cerebrovascular dilation is present after global cerebral ischemia (Clavier et al, 1994;Rosenblum and Wormley, 1995;Busija et al, 1996), but less is known about the effects of transient ischemia on microcirculatory response to vasoconstrictors. Our previous studies and those of others show that global ischemic brain injury can attenuate contractile responses to 5-HT (Watanabe et al, 2001;Fadyukova et al, 2004) and to arterial hypercapnia (Nelson et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…Striking endothelial defects in vasodilation and constriction have been described (Rosenblum, 1988;Dietrich, 1994;Rosenblum and Wormley, 1995;Cipolla et al, 1997;Watanabe et al, 2001). Platelets accumulate within the postischemic vasculature and contribute to hypoperfusion by mechanical obstruction and by secretion of the vasoconstrictors serotonin (5-HT) and thromboxane (TXA 2 ) from internal granules (Tanahashi et al, 1999;Garcia et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Estrogen Restores Postischemic Sensitivity to the Thromboxane Mimetic U46619 in Rat Pial Artery

Qin

Hurn

Littleton-Kearney

2005

J Cereb Blood Flow Metab

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The objectives of the study were to (1) characterize the dose-response relationship to the TXA 2 analog, U46619 (0.01, 0.1, and 1 lmol/L) after global cerebral ischemia, (2) determine whether chronic 17b-estradiol (E2) replacement alters this relationship, and (3) determine if E2's mechanisms are transduced through cognate estrogen receptors. Rats were assigned to five groups (n ¼ 6): placeboimplanted ovariectomized (OVX) females, OVX plus chronic E2 (CE), OVX plus acute E2 (AE), OVX plus chronic E2 plus the estrogen receptor inhibitor ICI 182,780 (CEI), and OVX plus acute E2 plus ICI 182,780 (AEI). Rats were anesthetized, intubated, cannulated (femoral artery and vein), fitted with a closed cranial window, and subjected to 15-min reversible forebrain ischemia (4-vessel occlusion, 4-VO) and 60 mins of reperfusion. Arterial blood gases, intrawindow pressure, and temperature were controlled. Vessel diameter was measured before and 5 mins after superfusion of each concentration of U46619. Compared with preischemic responses, contractile response to U46619 was depressed at all concentrations after ischemia in the OVX group. In the chronic E2 and acute E2 groups, contractile response to 1 lmol/L of U46619 was normalized to near baseline values. However, in the CEI and the AEI groups, postischemic vasoconstriction was similar to that observed in the OVX rats. We conclude that E2 targets the cerebral microvasculature to preserve postischemic pial artery reactivity and that the effect is receptor mediated. Restoration of normal constriction to vascular agonists may be an important mechanism by which E2 protects the vasculature and diminishes tissue damage after ischemia.

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Selective Depression of Endothelium-Dependent Dilations During Cerebral Ischemia

Cited by 16 publications

References 17 publications

Modulation of Basal and Postischemic Leukocyte-Endothelial Adherence by Nitric Oxide

Modulation of Basal and Postischemic Leukocyte-Endothelial Adherence by Nitric Oxide

In vivo reactive oxygen species production induced by ischemia in muscle arterioles of mice: involvement of xanthine oxidase and mitochondria

Estrogen Restores Postischemic Sensitivity to the Thromboxane Mimetic U46619 in Rat Pial Artery

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