Contribution of endothelin-1 to disruption of blood-brain barrier permeability in dogs

Narushima, Itaru; Kita, Taizo; Kubo, Kaoru; Yonetani, Yukio; Momochi, C.; Yoshikawa, I.; Shimada, Kaoru; Nakashima, Toshikatsu

doi:10.1007/s002109900137

Cited by 26 publications

(23 citation statements)

References 19 publications

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“…Another vascular hypothesis to investigate is related to the question of whether disruption of the blood-brain barrier (BBB) by ET-1 may promote the induction of CSD. Consistently, similar to vasoconstriction, BBB opening by ET-1 is mediated via ET A receptors (44,57). Furthermore, it has recently been shown that BBB disruption causes changes in neuronal excitability (53).…”

Section: Csd-like Depolarizations and A Penumbra-like Conditionmentioning

confidence: 80%

ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo

Kleeberg

Petzold

Major

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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. ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. Am J Physiol Heart Circ Physiol 286: H1339-H1346, 2004. First published December 4, 2003 10.1152 10. /ajpheart.00227.2003 has been shown that brain topical superfusion of endothelin (ET)-1 at concentrations around 100 nM induces repetitive cortical spreading depressions (CSDs) in vivo. It has remained unclear whether this effect of ET-1 is related to a primary neuronal/astroglial effect, such as an increase in neuronal excitability or induction of interastroglial calcium waves, or a penumbra-like condition after vasoconstriction. In vitro, ET-1 regulates interastroglial communication via combined activation of ETA and ETB receptors, whereas it induces vasoconstriction via single activation of ETA receptors. We have determined the ET receptor profile and intracellular signaling pathway of ET-1-induced CSDs in vivo. In contrast to the ETB receptor antagonist BQ-788 and concentration dependently, the ETA receptor antagonist BQ-123 completely blocked the occurrence of ET-1-induced CSDs. The ETB receptor antagonist did not increase the efficacy of the ETA receptor antagonist. Direct stimulation of ETB receptors with the selective ETB agonist BQ-3020 did not trigger CSDs. The phospholipase C (PLC) antagonist U-73122 inhibited CSD occurrence in contrast to the protein kinase C inhibitor Gö-6983. Our findings indicate that ET-1 induces CSDs through ETA receptor and PLC activation. We conclude that the induction of interastroglial calcium waves is unlikely the primary cause of ET-1-induced CSDs. On the basis of the receptor profile, likely primary targets of ET-1 mediating CSD are either neurons or vascular smooth muscle cells.endothelin-1; endothelin receptor antagonists; interastroglial calcium waves; gap junction communication; protein kinase C inhibition; arachidonic acid; cortical spreading depression ENDOTHELIN (ET)-1 was initially believed to influence brain functions only indirectly through regulation of cerebral perfusion due to its vasoconstrictor activity. However, over the past few years, evidence has accumulated that ET-1 may fulfill a wider range of physiological actions within the central nervous system (CNS), which has also led to its recognition as a neuropeptide (for reviews, see Refs. 33 and 36). Beside neurons, astrocytes represent a major ET target. Several studies have shown that ET-1 affects numerous cell functions of cultured astrocytes such as control of ion channel activity (5), glutamate efflux (52) and uptake (41), glucose utilization (58), permeability of gap junction communications (3, 16), and calcium signaling (3, 64). In turn, astrocytes are a major source of ET-1 (12, 13) and seem to play an important role in the regulation of ET-1 levels within the CNS (14,24,25).In contrast to the cerebrovascular system, in which ET A receptors are the major receptor subtype, astrocytes predominantly express the ET B receptor subtype (26,38). However, at least in cultured astrocytes, there ...

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Section: Csd-like Depolarizations and A Penumbra-like Conditionmentioning

confidence: 80%

ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo

Kleeberg

Petzold

Major

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…Significant BBB opening was found by Narushima et al (47) after intracisternal ET-1injection, considerably potentiated by a second injection. Several papers report that ET-1 stimulates COX-2 induction.…”

Section: Pro-inflammatory Effects Of Etsmentioning

confidence: 85%

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Sercombe

Dinh

Gomis

2002

Japanese Journal of Pharmacology

184

140

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ABSTRACT-Aneurysmal subarachnoid hemorrhage frequently results in complications including intracranial hypertension, rebleeding and vasospasm. The extravasated blood is responsible for a cascade of reactions involving release of various vasoactive and pro-inflammatory factors (several of which are purported to induce vasospasm) from blood and vascular components in the subarachnoid space. The authors review the available evidence linking these factors to the development of inflammatory lesions of the cerebral vasculature, emphasizing: 1) neurogenic inflammation due to massive release of sensory nerve neuropeptides; 2) hemoglobin from lysed erythrocytes, which creates functional lesions of endothelial and smooth muscle cells; 3) activity, expression and metabolites of lipoxygenases cyclooxygenases and nitric oxide synthases; 4) the possible role of endothelin-1 as a pro-inflammatory agent; 5) serotonin, histamine and bradykinin which are especially involved in blood-brain barrier disruption; 6) the prothrombotic and pro-inflammatory action of complement and thrombin towards endothelium; 7) the multiple actions of activated platelets, including platelet-derived growth factor production; 8) the presence of perivascular and intramural macrophages and granulocytes and their interaction with adhesion molecules; 9) the evolution, origins, and effects of pro-inflammatory cytokines, especially IL-1, TNF-a and IL-6. Human and animal studies on the use of anti-inflammatory agents in subarachnoid hemorrhage include superoxide and other radical scavengers, lipid peroxidation inhibitors, iron chelators, NSAIDs, glucocorticoids, and serine protease inhibitors. Many animal studies claim reduced vasospasm, but these effects are not always confirmed in human trials, where symptomatic vasospasm and outcome are the major endpoints. Despite recent work on penetrating vessel constriction, there is a paucity of studies on inflammatory markers in the microcirculation.

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“…ET-1 release has been shown to occur in many CNS disorders, including cerebral vasospasm/subarachnoid hemorrhage, stroke, human immunodeficiency virus encephalitis/ AIDS dementia complex, multiple sclerosis, and other inflammatory diseases of the brain (Levin, 1995;Nie and Olsson, 1996;Brooks et al, 1998;Narushima et al, 1999;Kedzierski and Yanagisawa, 2001;Didier et al, 2002). The literature contains conflicting reports as to the effects of ET-1 on brain capillary permeability.…”

Section: Regulation Of P-glycoprotein At the Blood-brain Barrier 391mentioning

confidence: 99%

Rapid Regulation of P-Glycoprotein at the Blood-Brain Barrier by Endothelin-1

Hartz

Bauer²,

Fricker³

et al. 2004

Mol Pharmacol

151

218

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The ATP-driven xenobiotic transporter P-glycoprotein is a critical element of the blood-brain barrier. To study regulation of P-glycoprotein function, we measured specific transport [(3Ј-oxo-4-butenyl-4-methyl-threonine(1), (valine(2)) cyclosporin (PSC833)-sensitive] of the fluorescent cyclosporin A derivative [N-⑀(4-nitrobenzofurazan-7-yl)-D-Lys 8 ]-cyclosporin A (NBDL-CSA) into the lumens of isolated rat brain capillaries using confocal microscopy and quantitative image analysis. Luminal NBDL-CSA accumulation was rapidly and reversibly reduced in a concentration-dependent manner by 0.1 to 100 nM endothelin-1 (ET-1). In this concentration range, ET-1 did not affect junctional permeability. The ET B receptor agonist sarafotoxin 6c also reduced transport. An ET B receptor antagonist blocked effects of ET-1 and sarafotoxin 6c; an ET A receptor antagonist was without effect. Consistent with this, immunostaining and Western blotting showed expression of the ET B receptor in brain capillary membranes. NBDL-CSA transport was also reduced by sodium nitroprusside, a NO donor, and by phorbol ester, a protein kinase C (PKC) activator. Inhibition of NO synthase (NOS) or PKC abolished the ET-1 effects. Thus, ET-1, acting through an ET B receptor, NOS, and PKC rapidly and reversibly reduced transport mediated by P-glycoprotein at the blood-brain barrier.The structural basis of the blood-brain barrier is the nonfenestrated, brain capillary endothelium. Functionally, low passive permeability and the expression of selective, plasma membrane-bound transporters define this barrier tissue. These combine to both nourish the central nervous system (CNS) and protect it from potentially toxic chemicals. One critical selective component of the blood-brain barrier is Pglycoprotein, an ATP-driven, drug-efflux pump (Schinkel et al., 1994). This multispecific, primary active transporter, located at the luminal membrane of the brain capillary endothelium, is considered to be an important "gatekeeper" of the blood-brain barrier (Schinkel, 1999). As such, it protects the CNS from neurotoxicants and also limits brain penetration of a large number of drugs used to treat CNS disorders (Schinkel et al., 1996). In this regard, reduced P-glycoprotein function, whether the result of pump inhibition, genetic manipulation, or pathological change, substantially increases brain levels of administered drugs, including chemotherapeutics, human immunodeficiency virus protease inhibitors, anticonvulsants, antipsychotics, and glucocorticoids (Schinkel et al., 1996;Fellner et al., 2002;Goralski et al., 2003).For CNS therapy, it would clearly be advantageous to be able to modulate P-glycoprotein function over the short term while still retaining its protection over the longer term. One strategy that may accomplish this would be to transiently decrease specific efflux to the blood through rapid regulation. Unfortunately, we know little about the regulation of Pglycoprotein at the blood-brain barrier, and what we do know concerns mechanisms that take fro...

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Contribution of endothelin-1 to disruption of blood-brain barrier permeability in dogs

Cited by 26 publications

References 19 publications

ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo

ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Rapid Regulation of P-Glycoprotein at the Blood-Brain Barrier by Endothelin-1

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Contribution of endothelin-1 to disruption of blood-brain barrier permeability in dogs

Cited by 26 publications

References 19 publications

ET-1 induces cortical spreading depression via activation of the ETAreceptor/phospholipase C pathway in vivo

ET-1 induces cortical spreading depression via activation of the ETAreceptor/phospholipase C pathway in vivo

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Rapid Regulation of P-Glycoprotein at the Blood-Brain Barrier by Endothelin-1

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Product

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ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo

ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo