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      Mechanism of ATP-Induced Local and Conducted Vasomotor Responses in Isolated Rat Cerebral Penetrating Arterioles

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          Abstract

          Background: Adenosine triphosphate (ATP), a potent vascular regulator in the cerebral circulation, initiates conducted vasomotor responses which may be impaired after pathological insults. We analyzed the mechanism of ATP-induced local vasomotor responses and their effect on conducted vasomotor responses in rat cerebral penetrating arterioles. Methods: Arterioles were cannulated and their internal diameter monitored. Vasomotor responses to ATP were observed in the presence or absence of inhibitors, or after endothelial impairment. Smooth muscle membrane potentials were measured in some vessels. Results: Microapplication of ATP produced a biphasic response (constriction followed by dilation), which resulted in conducted dilation preceded by a membrane hyperpolarization. α,β-methylene-ATP or pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) blunted the ATP-mediated constriction and enhanced local and conducted dilation. N<sup>ω</sup>-monomethyl- L-arginine, endothelial impairment and N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH) reduced the local dilation caused by ATP. The conducted dilation was attenuated by MS-PPOH and endothelial impairment, but not N<sup>ω</sup>-monomethyl- L-arginine or indomethacin. Conclusion: ATP-induced conducted dilation is preceded by membrane hyperpolarization. Local ATP induces initial local constriction via smooth-muscle P<sub>2X1</sub> and subsequent dilation via endothelial P<sub>2Y</sub> receptors. Nitric oxide, cytochrome P450 metabolites, and intermediate and large conductance K<sub>Ca</sub> channels mediate dilation caused by ATP. ATP-induced conducted dilation is dependent upon both the endothelium and cytochrome P450 metabolites.

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          Most cited references 10

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          Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling.

          Neuronal activity in the brain is thought to be coupled to cerebral arterioles (functional hyperemia) through Ca2+ signals in astrocytes. Although functional hyperemia occurs rapidly, within seconds, such rapid signaling has not been demonstrated in situ, and Ca2+ measurements in parenchymal arterioles are still lacking. Using a laser scanning confocal microscope and fluorescence Ca2+ indicators, we provide the first evidence that in a brain slice preparation, increased neuronal activity by electrical stimulation (ES) is rapidly signaled, within seconds, to cerebral arterioles and is associated with astrocytic Ca2+ waves. Smooth muscle cells in parenchymal arterioles exhibited Ca2+ and diameter oscillations ("vasomotion") that were rapidly suppressed by ES. The neuronal-mediated Ca2+ rise in cortical astrocytes was dependent on intracellular (inositol trisphosphate [IP3]) and extracellular voltage-dependent Ca2+ channel sources. The Na+ channel blocker tetrodotoxin prevented the rise in astrocytic [Ca2+]i and the suppression of Ca2+ oscillations in parenchymal arterioles to ES, indicating that neuronal activity was necessary for both events. Activation of metabotropic glutamate receptors in astrocytes significantly decreased the frequency of Ca2+ oscillations in parenchymal arterioles. This study supports the concept that astrocytic Ca2+ changes signal the cerebral microvasculature and indicate the novel concept that this communication occurs through the suppression of arteriolar [Ca2+]i oscillations and corresponding vasomotion. The full text of this article is available online at http://circres.ahajournals.org.
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            Conducted vascular responses: communication across the capillary bed.

            Conducted vasomotor responses are important for the effective distribution of blood flow, although the mechanism by which these responses are initiated is not well understood. ATP, a substance which is released from circulating red blood cells in response to low PO2 and low pH, two conditions which are associated with decreased supply relative to demand, has been shown to initiate conducted vasodilation following its intraluminal application in first and second order arterioles. Since such low PO2 and low pH conditions would most likely occur on the venous side of the vasculature, we evaluated the response of the arteriolar and capillary networks to application of ATP into venules in the Saran-covered hamster cheek pouch retractor muscle using in vivo video microscopy. Intraluminal application of 40 and 400 pl of 10(-6) M ATP resulted in dose-dependent increases in arteriolar diameter > 450 microm upstream from the site of application. These changes in arteriolar diameter were accompanied by significant increases in red blood cell flux. In capillaries, red blood cell flux doubled in response to ATP administration. Since NO was previously determined to be involved in the vascular response to intraluminal ATP in arterioles, we evaluated its role in these responses. We found that systemic administration of l-NAME prior to ATP application eliminated any conducted response and this effect of l-NAME was reversed by the systemic administration of l-arginine. These data suggest that ATP, which is released from red blood cells in response to low PO2 and low pH, conditions which would be found in the venular microvasculature, may serve a role in distributing perfusion in response to alterations in supply. Copyright 1998 Academic Press.
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              Arachidonic acid metabolites, hydrogen peroxide, and EDHF in cerebral arteries.

              We tested the hypotheses that EDHF in rat middle cerebral arteries (MCAs) involves 1) metabolism of arachidonic acid through the epoxygenase pathway, 2) metabolism of arachidonic acid through the lipoxygenase pathway, or 3) reactive oxygen species. EDHF-mediated dilations were elicited in isolated and pressurized rat MCAs by activation of endothelial P2Y(2) receptors with either UTP or ATP. All studies were conducted after the inhibition of nitric oxide synthase and cyclooxygenase with N(omega)-nitro-l-arginine methyl ester (10 microM) and indomethacin (10 microM), respectively. The inhibition of epoxygenase with miconazole (30 microM) did not alter EDHF dilations to UTP, whereas the structurally different epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanoic acid (20 or 40 microM) only modestly inhibited EDHF at the highest concentration of UTP. An antagonist of epoxyeicosatrienoic acids, 14,15-epoxyeicosa-5(Z)-enoic acid, had no effect on EDHF dilations to UTP. Chronic inhibition of epoxygenase in the rat with 1-aminobenzotriazol (50 mg/kg twice daily for 5 days) did not alter EDHF dilations. The inhibition of the lipoxygenase pathway with either 10 microM baicalein or 10 microM nordihydroguaiaretic acid produced no major inhibitory effects on EDHF dilations. The combination of superoxide dismutase (200 U/ml) and catalase (140 U/ml) had no effect on EDHF dilations. Neither tiron (10 mM), a cell-permeable scavenger of reactive oxygen species, nor deferoxamine (1 or 10 mM), an iron chelator that blocks the formation of hydroxyl radicals, altered EDHF dilations in rat MCAs. We conclude that EDHF dilations in the rat MCA do not involve the epoxygenase pathway, lipoxygenase pathway, or reactive oxygen species including H(2)O(2).
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2009
                April 2009
                04 November 2008
                : 46
                : 3
                : 253-264
                Affiliations
                aDepartment of Neurosurgery, and bHope Center, Washington University School of Medicine, St. Louis, Mo.; cDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Tex., USA; dDepartment of Neurosurgery, Shinshu University School of Medicine, Matsumoto, Japan
                Article
                167273 J Vasc Res 2009;46:253–264
                10.1159/000167273
                2673330
                18984964
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, References: 32, Pages: 12
                Categories
                Research Paper

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