Blood–brain barrier transport studies of organic guanidino cations using an in situ brain perfusion technique
Blood–brain barrier (BBB) transport of essential polar substrates is mediated by specific, carrier-mediated transport proteins. The BBB transport mechanisms for polar compounds with terminal guanidino functional groups (R–NHC(NH)NH 2) are not well defined. The goal of the present work was to investi...
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| Veröffentlicht in: | Brain research 2000-09, Vol.876 (1), p.141-147 |
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| creator | Mahar Doan, Kelly M Lakhman, Sukhwinder S Boje, Kathleen M.K |
| description | Blood–brain barrier (BBB) transport of essential polar substrates is mediated by specific, carrier-mediated transport proteins. The BBB transport mechanisms for polar compounds with terminal guanidino functional groups (R–NHC(NH)NH
2) are not well defined. The goal of the present work was to investigate the BBB transport mechanism(s) for terminal guanidino substrates using an in situ brain perfusion technique. Brain region radiotracer influx clearance (Cl
in) was calculated for representative guanidino substrates, [
14C]
l-arginine, [
14C]aminoguanidine and [
14C]guanidine, in the presence or absence of excess terminal guanidino analogues. The Cl
in for [
14C]
l-arginine (0.21±0.0094 cm
3/min/g wet brain weight, mean±S.E.M.,
n=four rats) was significantly decreased by 1000× concentrations of unlabeled
l-arginine,
N
G-methyl-
l-arginine,
N
G-,
N
G-dimethyl-
l-arginine and
N
G-amino-
l-arginine by ∼83% (
P |
| doi_str_mv | 10.1016/S0006-8993(00)02643-3 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_72232471</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006899300026433</els_id><sourcerecordid>72232471</sourcerecordid><originalsourceid>FETCH-LOGICAL-c421t-2fac2a6ab16681f6cfda64cf426114c7e25fa747d91d64f546442567203113563</originalsourceid><addsrcrecordid>eNqFkctuFDEQRS1ERIbAJ4C8QAgWHcqPtqdXEYnyQIqUBbC2PH4MRj32YLuRsuMf8of5EjzpEWGXVcnyqXtL9yL0hsAxASI-fQUA0S2HgX0A-AhUcNaxZ2hBlpJ2gnJ4jhb_kEP0spSf7cnYAC_QIYFBMgF0gdLpmJK9_3O3yjpEvNI5B5dxzTqWbcoVlzrZ4ApOHqe81jEYvJ7asCEmbHQNKRY8lRDXWEfcJEqoE57Vti779pUirs78iOHX5F6hA6_H4l7v5xH6fnH-7eyqu765_HL2-boznJLaUa8N1UKviBBL4oXxVgtuPKeCEG6ko73Xkks7ECu477ngnPZCUmCEsF6wI_R-1t3m1GxLVZtQjBtHHV2aipKUMsoleRIksjkupWxgP4Mmp1Ky82qbw0bnW0VA7SpRD5WoXd4KQD1Uoljbe7s3mFYbZ__bmjtowLs9oIvRo2_Rm1AeuR7IwHc6JzPmWmy_W0mqmOCicTZkZ6qyKTxxyV8JuqmT</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17611877</pqid></control><display><type>article</type><title>Blood–brain barrier transport studies of organic guanidino cations using an in situ brain perfusion technique</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Mahar Doan, Kelly M ; Lakhman, Sukhwinder S ; Boje, Kathleen M.K</creator><creatorcontrib>Mahar Doan, Kelly M ; Lakhman, Sukhwinder S ; Boje, Kathleen M.K</creatorcontrib><description>Blood–brain barrier (BBB) transport of essential polar substrates is mediated by specific, carrier-mediated transport proteins. The BBB transport mechanisms for polar compounds with terminal guanidino functional groups (R–NHC(NH)NH
2) are not well defined. The goal of the present work was to investigate the BBB transport mechanism(s) for terminal guanidino substrates using an in situ brain perfusion technique. Brain region radiotracer influx clearance (Cl
in) was calculated for representative guanidino substrates, [
14C]
l-arginine, [
14C]aminoguanidine and [
14C]guanidine, in the presence or absence of excess terminal guanidino analogues. The Cl
in for [
14C]
l-arginine (0.21±0.0094 cm
3/min/g wet brain weight, mean±S.E.M.,
n=four rats) was significantly decreased by 1000× concentrations of unlabeled
l-arginine,
N
G-methyl-
l-arginine,
N
G-,
N
G-dimethyl-
l-arginine and
N
G-amino-
l-arginine by ∼83% (
P<0.01;
n=4–5), whereas 1000× concentrations of nitro-
l-arginine, aminoguanidine and guanidine were without effect. In contrast, the respective Cl
in of [
14C]aminoguanidine and [
14C]guanidine (0.0085±0.00039 and 0.015±0.0015 cm
3/min/g,
n=4, respectively) were not significantly decreased by 1000× concentrations of unlabeled aminoguanidine or guanidine. The Cl
in values for all [
14C]guanidino probes were significantly greater (
P<0.05) from that of [
3H]inulin, a marker of cerebrovascular blood volume. These data suggest that the hydrophilic guanidino cations aminoguanidine and guanidine penetrate the BBB by a minor diffusional process with no appreciable transport via saturable processes. In contrast, BBB penetration of
l-arginine occurs via the saturable basic amino acid transporter that has specificity for amino acid analogues possessing cationic terminal guanidino groups.</description><identifier>ISSN: 0006-8993</identifier><identifier>EISSN: 1872-6240</identifier><identifier>DOI: 10.1016/S0006-8993(00)02643-3</identifier><identifier>PMID: 10973602</identifier><identifier>CODEN: BRREAP</identifier><language>eng</language><publisher>London: Elsevier B.V</publisher><subject>Amino Acid Transport Systems ; amino acid transporter ; Aminoguanidine ; Animals ; Biological and medical sciences ; Biological Transport ; Blood-Brain Barrier ; Brain - metabolism ; Carrier Proteins - metabolism ; Cationic amino acids ; Cations - metabolism ; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges ; Fundamental and applied biological sciences. Psychology ; Guanidine - metabolism ; Guanidines - metabolism ; guanidino ; In situ brain perfusion ; Inulin - metabolism ; Male ; Organic cation ; Perfusion ; Rats ; Rats, Sprague-Dawley ; Substrate Specificity ; Transport ; Vertebrates: nervous system and sense organs</subject><ispartof>Brain research, 2000-09, Vol.876 (1), p.141-147</ispartof><rights>2000 Elsevier Science B.V.</rights><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-2fac2a6ab16681f6cfda64cf426114c7e25fa747d91d64f546442567203113563</citedby><cites>FETCH-LOGICAL-c421t-2fac2a6ab16681f6cfda64cf426114c7e25fa747d91d64f546442567203113563</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006899300026433$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1501943$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10973602$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mahar Doan, Kelly M</creatorcontrib><creatorcontrib>Lakhman, Sukhwinder S</creatorcontrib><creatorcontrib>Boje, Kathleen M.K</creatorcontrib><title>Blood–brain barrier transport studies of organic guanidino cations using an in situ brain perfusion technique</title><title>Brain research</title><addtitle>Brain Res</addtitle><description>Blood–brain barrier (BBB) transport of essential polar substrates is mediated by specific, carrier-mediated transport proteins. The BBB transport mechanisms for polar compounds with terminal guanidino functional groups (R–NHC(NH)NH
2) are not well defined. The goal of the present work was to investigate the BBB transport mechanism(s) for terminal guanidino substrates using an in situ brain perfusion technique. Brain region radiotracer influx clearance (Cl
in) was calculated for representative guanidino substrates, [
14C]
l-arginine, [
14C]aminoguanidine and [
14C]guanidine, in the presence or absence of excess terminal guanidino analogues. The Cl
in for [
14C]
l-arginine (0.21±0.0094 cm
3/min/g wet brain weight, mean±S.E.M.,
n=four rats) was significantly decreased by 1000× concentrations of unlabeled
l-arginine,
N
G-methyl-
l-arginine,
N
G-,
N
G-dimethyl-
l-arginine and
N
G-amino-
l-arginine by ∼83% (
P<0.01;
n=4–5), whereas 1000× concentrations of nitro-
l-arginine, aminoguanidine and guanidine were without effect. In contrast, the respective Cl
in of [
14C]aminoguanidine and [
14C]guanidine (0.0085±0.00039 and 0.015±0.0015 cm
3/min/g,
n=4, respectively) were not significantly decreased by 1000× concentrations of unlabeled aminoguanidine or guanidine. The Cl
in values for all [
14C]guanidino probes were significantly greater (
P<0.05) from that of [
3H]inulin, a marker of cerebrovascular blood volume. These data suggest that the hydrophilic guanidino cations aminoguanidine and guanidine penetrate the BBB by a minor diffusional process with no appreciable transport via saturable processes. In contrast, BBB penetration of
l-arginine occurs via the saturable basic amino acid transporter that has specificity for amino acid analogues possessing cationic terminal guanidino groups.</description><subject>Amino Acid Transport Systems</subject><subject>amino acid transporter</subject><subject>Aminoguanidine</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biological Transport</subject><subject>Blood-Brain Barrier</subject><subject>Brain - metabolism</subject><subject>Carrier Proteins - metabolism</subject><subject>Cationic amino acids</subject><subject>Cations - metabolism</subject><subject>Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Guanidine - metabolism</subject><subject>Guanidines - metabolism</subject><subject>guanidino</subject><subject>In situ brain perfusion</subject><subject>Inulin - metabolism</subject><subject>Male</subject><subject>Organic cation</subject><subject>Perfusion</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Substrate Specificity</subject><subject>Transport</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0006-8993</issn><issn>1872-6240</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctuFDEQRS1ERIbAJ4C8QAgWHcqPtqdXEYnyQIqUBbC2PH4MRj32YLuRsuMf8of5EjzpEWGXVcnyqXtL9yL0hsAxASI-fQUA0S2HgX0A-AhUcNaxZ2hBlpJ2gnJ4jhb_kEP0spSf7cnYAC_QIYFBMgF0gdLpmJK9_3O3yjpEvNI5B5dxzTqWbcoVlzrZ4ApOHqe81jEYvJ7asCEmbHQNKRY8lRDXWEfcJEqoE57Vti779pUirs78iOHX5F6hA6_H4l7v5xH6fnH-7eyqu765_HL2-boznJLaUa8N1UKviBBL4oXxVgtuPKeCEG6ko73Xkks7ECu477ngnPZCUmCEsF6wI_R-1t3m1GxLVZtQjBtHHV2aipKUMsoleRIksjkupWxgP4Mmp1Ky82qbw0bnW0VA7SpRD5WoXd4KQD1Uoljbe7s3mFYbZ__bmjtowLs9oIvRo2_Rm1AeuR7IwHc6JzPmWmy_W0mqmOCicTZkZ6qyKTxxyV8JuqmT</recordid><startdate>20000908</startdate><enddate>20000908</enddate><creator>Mahar Doan, Kelly M</creator><creator>Lakhman, Sukhwinder S</creator><creator>Boje, Kathleen M.K</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20000908</creationdate><title>Blood–brain barrier transport studies of organic guanidino cations using an in situ brain perfusion technique</title><author>Mahar Doan, Kelly M ; Lakhman, Sukhwinder S ; Boje, Kathleen M.K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-2fac2a6ab16681f6cfda64cf426114c7e25fa747d91d64f546442567203113563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Amino Acid Transport Systems</topic><topic>amino acid transporter</topic><topic>Aminoguanidine</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biological Transport</topic><topic>Blood-Brain Barrier</topic><topic>Brain - metabolism</topic><topic>Carrier Proteins - metabolism</topic><topic>Cationic amino acids</topic><topic>Cations - metabolism</topic><topic>Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Guanidine - metabolism</topic><topic>Guanidines - metabolism</topic><topic>guanidino</topic><topic>In situ brain perfusion</topic><topic>Inulin - metabolism</topic><topic>Male</topic><topic>Organic cation</topic><topic>Perfusion</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Substrate Specificity</topic><topic>Transport</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mahar Doan, Kelly M</creatorcontrib><creatorcontrib>Lakhman, Sukhwinder S</creatorcontrib><creatorcontrib>Boje, Kathleen M.K</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Brain research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mahar Doan, Kelly M</au><au>Lakhman, Sukhwinder S</au><au>Boje, Kathleen M.K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Blood–brain barrier transport studies of organic guanidino cations using an in situ brain perfusion technique</atitle><jtitle>Brain research</jtitle><addtitle>Brain Res</addtitle><date>2000-09-08</date><risdate>2000</risdate><volume>876</volume><issue>1</issue><spage>141</spage><epage>147</epage><pages>141-147</pages><issn>0006-8993</issn><eissn>1872-6240</eissn><coden>BRREAP</coden><abstract>Blood–brain barrier (BBB) transport of essential polar substrates is mediated by specific, carrier-mediated transport proteins. The BBB transport mechanisms for polar compounds with terminal guanidino functional groups (R–NHC(NH)NH
2) are not well defined. The goal of the present work was to investigate the BBB transport mechanism(s) for terminal guanidino substrates using an in situ brain perfusion technique. Brain region radiotracer influx clearance (Cl
in) was calculated for representative guanidino substrates, [
14C]
l-arginine, [
14C]aminoguanidine and [
14C]guanidine, in the presence or absence of excess terminal guanidino analogues. The Cl
in for [
14C]
l-arginine (0.21±0.0094 cm
3/min/g wet brain weight, mean±S.E.M.,
n=four rats) was significantly decreased by 1000× concentrations of unlabeled
l-arginine,
N
G-methyl-
l-arginine,
N
G-,
N
G-dimethyl-
l-arginine and
N
G-amino-
l-arginine by ∼83% (
P<0.01;
n=4–5), whereas 1000× concentrations of nitro-
l-arginine, aminoguanidine and guanidine were without effect. In contrast, the respective Cl
in of [
14C]aminoguanidine and [
14C]guanidine (0.0085±0.00039 and 0.015±0.0015 cm
3/min/g,
n=4, respectively) were not significantly decreased by 1000× concentrations of unlabeled aminoguanidine or guanidine. The Cl
in values for all [
14C]guanidino probes were significantly greater (
P<0.05) from that of [
3H]inulin, a marker of cerebrovascular blood volume. These data suggest that the hydrophilic guanidino cations aminoguanidine and guanidine penetrate the BBB by a minor diffusional process with no appreciable transport via saturable processes. In contrast, BBB penetration of
l-arginine occurs via the saturable basic amino acid transporter that has specificity for amino acid analogues possessing cationic terminal guanidino groups.</abstract><cop>London</cop><cop>Amsterdam</cop><cop>New York, NY</cop><pub>Elsevier B.V</pub><pmid>10973602</pmid><doi>10.1016/S0006-8993(00)02643-3</doi><tpages>7</tpages></addata></record> |
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| subjects | Amino Acid Transport Systems amino acid transporter Aminoguanidine Animals Biological and medical sciences Biological Transport Blood-Brain Barrier Brain - metabolism Carrier Proteins - metabolism Cationic amino acids Cations - metabolism Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges Fundamental and applied biological sciences. Psychology Guanidine - metabolism Guanidines - metabolism guanidino In situ brain perfusion Inulin - metabolism Male Organic cation Perfusion Rats Rats, Sprague-Dawley Substrate Specificity Transport Vertebrates: nervous system and sense organs |
| title | Blood–brain barrier transport studies of organic guanidino cations using an in situ brain perfusion technique |
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