| Differential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebral C6 gliomas. | |
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MedLine Citation:
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PMID: 21041233 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Nitric oxide (NO) signaling in tumors and endothelial cells regulates vascular permeability and blood flow and therefore influences tumor uptake and response to therapeutic compounds. As delivery and efficacy of chemotherapy is impaired in CNS neoplasms due to a partially intact blood-brain barrier (BBB), we studied the effects of NO released by the short-acting NO donor disodium 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate methanolate (PROLI/NO) on BBB integrity and blood flow in C6 gliomas using [¹⁴C]-aminoisobutyric acid (AIB) and [¹⁴C]-iodoantipyrine quantitative autoradiography. PROLI/NO selectively increased intratumoral uptake of [¹⁴C]AIB and [¹⁴C]sucrose when given as a 3-minute intracarotid infusion or a 15-minute i.v. infusion (AIB: tumor, K₁ = 68.7 ± 3.2 vs 24.9 ± 0.9 µL g⁻¹ min⁻¹, P < .0001; sucrose, K₁ = 16.9 ± 0.9 vs 11.5 ± 0.9 µL g⁻¹ min⁻¹, P = .0007). This effect was achieved without significant changes in cerebral and tumor blood flow or arterial blood pressure, which indicates that the effect on vascular permeability is independent of changes in vascular tone induced by NO. This effect was mediated by activation of the NO/3',5'-cyclic guanosine monophosphate (cGMP) pathway, as it was blocked by guanylate cyclase inhibition by LY83583 and reproduced by the delivery of 8-bromoguanosine 5'-monophosphate or inhibition of cGMP degradation by the phosphodiesterase inhibitor zaprinast. Inhibition of inducible NO synthase by aminoguanidine or cyclooxygenase inhibition by indometacin or dexamethasone did not reduce the blood-tumor barrier (BTB) response to PROLI/NO. PROLI/NO, and perhaps other NO-donating compounds, can be used to selectively increase BTB permeability in gliomas through the NO/cGMP pathway at doses that do not cause unwanted vasodilatory changes in blood flow and that do not affect the systemic circulation. |
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Authors:
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Astrid Weyerbrock; Stuart Walbridge; Joseph E Saavedra; Larry K Keefer; Edward H Oldfield |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural Date: 2010-11-01 |
Journal Detail:
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Title: Neuro-oncology Volume: 13 ISSN: 1523-5866 ISO Abbreviation: Neuro-oncology Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-18 Completed Date: 2011-05-09 Revised Date: 2012-02-01 |
Medline Journal Info:
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Nlm Unique ID: 100887420 Medline TA: Neuro Oncol Country: United States |
Other Details:
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Languages: eng Pagination: 203-11 Citation Subset: IM |
Affiliation:
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Department of Neurosurgery, University Medical Center Freiburg, Breisacher Strasse 64, D-79106 Freiburg, Germany. astrid.weyerbrock@uniklinik-freiburg.de |
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| MeSH Terms | |
Descriptor/Qualifier:
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3',5'-Cyclic-GMP Phosphodiesterases
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antagonists & inhibitors Animals Blood-Brain Barrier / drug effects* Brain Neoplasms / blood supply, drug therapy*, metabolism Bronchodilator Agents / pharmacology* Capillary Permeability / drug effects Cerebrovascular Circulation / drug effects* Glioma / blood supply, drug therapy*, metabolism Guanosine / analogs & derivatives, pharmacology Male Nitric Oxide / pharmacology* Nitric Oxide Donors / pharmacology* Phosphodiesterase Inhibitors / pharmacology Proline / analogs & derivatives, pharmacology Purinones / pharmacology Rats Rats, Sprague-Dawley |
| Chemical | |
Reg. No./Substance:
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0/Bronchodilator Agents; 0/Nitric Oxide Donors; 0/Phosphodiesterase Inhibitors; 0/Purinones; 0/proline-nitric oxide; 10102-43-9/Nitric Oxide; 118-00-3/Guanosine; 147-85-3/Proline; 37762-06-4/zaprinast; 4016-63-1/8-bromoguanosine; EC 3.1.4.35/3',5'-Cyclic-GMP Phosphodiesterases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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