Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt
Vasorelaxation to beta(2)-adrenoceptor stimulation occurs through both endothelium-dependent and endothelium-independent mechanisms, and the former is mediated through Ca(2+)-independent activation of endothelial-type nitric oxide synthase (NOS-3). Since Ca(2+)-independent NOS-3 activation may occur...
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| Veröffentlicht in: | British journal of pharmacology 2004-10, Vol.143 (3), p.397-403 |
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| creator | Ferro, Albert Coash, Marcy Yamamoto, Takahiro Rob, Jubli Ji, Yong Queen, Lindsay |
| description | Vasorelaxation to beta(2)-adrenoceptor stimulation occurs through both endothelium-dependent and endothelium-independent mechanisms, and the former is mediated through Ca(2+)-independent activation of endothelial-type nitric oxide synthase (NOS-3). Since Ca(2+)-independent NOS-3 activation may occur through its serine phosphorylation via protein kinase A (PKA) or Akt, we determined the PKA and Akt dependency of beta(2)-adrenergic relaxation of rat aorta. Rat aortic rings were pre-incubated with the PKA inhibitor H-89 (10(-7) m), the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (5 x 10(-7) m), Akt inhibitor (10(-5) m), or vehicle, in the absence or presence of the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 10(-4) m). Rings were then contracted with phenylephrine (10(-7) m), and concentration-relaxation responses determined to the beta(2)-adrenoceptor agonist albuterol. Rings exhibited a concentration-dependent relaxation to albuterol: pEC(50) 6.9+/-0.2, E(max) 88.2+/-4.0%. l-NAME attenuated E(max) to 60.2+/-3.5% (P |
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Since Ca(2+)-independent NOS-3 activation may occur through its serine phosphorylation via protein kinase A (PKA) or Akt, we determined the PKA and Akt dependency of beta(2)-adrenergic relaxation of rat aorta. Rat aortic rings were pre-incubated with the PKA inhibitor H-89 (10(-7) m), the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (5 x 10(-7) m), Akt inhibitor (10(-5) m), or vehicle, in the absence or presence of the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 10(-4) m). Rings were then contracted with phenylephrine (10(-7) m), and concentration-relaxation responses determined to the beta(2)-adrenoceptor agonist albuterol. Rings exhibited a concentration-dependent relaxation to albuterol: pEC(50) 6.9+/-0.2, E(max) 88.2+/-4.0%. l-NAME attenuated E(max) to 60.2+/-3.5% (P<0.001). In the presence of l-NAME, wortmannin or Akt inhibitor did not influence albuterol responses, whereas H-89 reduced E(max) further, to 27.5+/-2.2% (P<0.001). In the absence of l-NAME, E(max) to albuterol was reduced by H-89, wortmannin or Akt inhibitor, to 56.2+/-2.2, 56.0+/-1.6 and 55.4+/-1.8%, respectively (P<0.001 for each); the combinations H-89 plus wortmannin or H-89 plus Akt inhibitor reduced E(max) further still. Western blotting of NOS-3 immunoprecipitates from rat aortas confirmed that albuterol increased serine phosphorylation of NOS-3, and this increase was attenuated by H-89 or Akt inhibitor. Our results indicate that beta(2)-adrenoceptor stimulation relaxes rat aorta through both NO-dependent and independent mechanisms. The latter is predominantly PKA-mediated, whereas the former occurs through both PKA and PI3K/Akt activation.</description><identifier>ISSN: 0007-1188</identifier><identifier>PMID: 15351777</identifier><language>eng</language><publisher>England</publisher><subject>Adrenergic beta-2 Receptor Agonists ; Adrenergic beta-Agonists - pharmacology ; Adrenergic beta-Antagonists - pharmacology ; Albuterol - pharmacology ; Androstadienes - pharmacology ; Animals ; Aorta, Thoracic - drug effects ; Aorta, Thoracic - physiology ; Blotting, Western ; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation - drug effects ; Enzyme Inhibitors - pharmacology ; In Vitro Techniques ; Isoproterenol - pharmacology ; Isoquinolines - pharmacology ; Male ; NG-Nitroarginine Methyl Ester - pharmacology ; Nitric Oxide - metabolism ; Nitric Oxide Synthase - antagonists & inhibitors ; Nitric Oxide Synthase - metabolism ; Phenylephrine - pharmacology ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - metabolism ; Propanolamines - pharmacology ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt ; Rats ; Rats, Wistar ; Receptors, Adrenergic, beta-2 - physiology ; Sulfonamides - pharmacology ; Vasodilation - drug effects ; Vasodilation - physiology</subject><ispartof>British journal of pharmacology, 2004-10, Vol.143 (3), p.397-403</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15351777$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferro, Albert</creatorcontrib><creatorcontrib>Coash, Marcy</creatorcontrib><creatorcontrib>Yamamoto, Takahiro</creatorcontrib><creatorcontrib>Rob, Jubli</creatorcontrib><creatorcontrib>Ji, Yong</creatorcontrib><creatorcontrib>Queen, Lindsay</creatorcontrib><title>Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Vasorelaxation to beta(2)-adrenoceptor stimulation occurs through both endothelium-dependent and endothelium-independent mechanisms, and the former is mediated through Ca(2+)-independent activation of endothelial-type nitric oxide synthase (NOS-3). Since Ca(2+)-independent NOS-3 activation may occur through its serine phosphorylation via protein kinase A (PKA) or Akt, we determined the PKA and Akt dependency of beta(2)-adrenergic relaxation of rat aorta. Rat aortic rings were pre-incubated with the PKA inhibitor H-89 (10(-7) m), the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (5 x 10(-7) m), Akt inhibitor (10(-5) m), or vehicle, in the absence or presence of the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 10(-4) m). Rings were then contracted with phenylephrine (10(-7) m), and concentration-relaxation responses determined to the beta(2)-adrenoceptor agonist albuterol. Rings exhibited a concentration-dependent relaxation to albuterol: pEC(50) 6.9+/-0.2, E(max) 88.2+/-4.0%. l-NAME attenuated E(max) to 60.2+/-3.5% (P<0.001). In the presence of l-NAME, wortmannin or Akt inhibitor did not influence albuterol responses, whereas H-89 reduced E(max) further, to 27.5+/-2.2% (P<0.001). In the absence of l-NAME, E(max) to albuterol was reduced by H-89, wortmannin or Akt inhibitor, to 56.2+/-2.2, 56.0+/-1.6 and 55.4+/-1.8%, respectively (P<0.001 for each); the combinations H-89 plus wortmannin or H-89 plus Akt inhibitor reduced E(max) further still. Western blotting of NOS-3 immunoprecipitates from rat aortas confirmed that albuterol increased serine phosphorylation of NOS-3, and this increase was attenuated by H-89 or Akt inhibitor. Our results indicate that beta(2)-adrenoceptor stimulation relaxes rat aorta through both NO-dependent and independent mechanisms. The latter is predominantly PKA-mediated, whereas the former occurs through both PKA and PI3K/Akt activation.</description><subject>Adrenergic beta-2 Receptor Agonists</subject><subject>Adrenergic beta-Agonists - pharmacology</subject><subject>Adrenergic beta-Antagonists - pharmacology</subject><subject>Albuterol - pharmacology</subject><subject>Androstadienes - pharmacology</subject><subject>Animals</subject><subject>Aorta, Thoracic - drug effects</subject><subject>Aorta, Thoracic - physiology</subject><subject>Blotting, Western</subject><subject>Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Isoproterenol - pharmacology</subject><subject>Isoquinolines - pharmacology</subject><subject>Male</subject><subject>NG-Nitroarginine Methyl Ester - pharmacology</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase - antagonists & inhibitors</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Phenylephrine - pharmacology</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Propanolamines - pharmacology</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, Adrenergic, beta-2 - physiology</subject><subject>Sulfonamides - pharmacology</subject><subject>Vasodilation - drug effects</subject><subject>Vasodilation - physiology</subject><issn>0007-1188</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kD9PwzAUxDOAaCl8BeSJLZIdO3EyVhX_pAqW7tFz_NqapnawXxBMfHUitTCddPrpdHcX2ZxzrnMh6nqWXaf0zrlQWpdX2UyUshRa63n28-oouo6FL2cxtzigt-iJGSQocrARPcbdBFjXAwG54FnYsgjEIEQC5hI7onVAaBntYxh3ewYduc9_1gTasyEGQufZwXlIyJYMvGXLA91kl1voE96edZFtHh82q-d8_fb0slqu86FUOm9M11TWGtnxulaKKw4CVYMKTakUSjDT1EJUUnFueCH1ZNsOCzTS2qKp5SK7P8VOPT5GTNQeXeqw78FjGFNbVY0qhNQTeHcGRzPtaofojhC_27_H5C9_dWfM</recordid><startdate>200410</startdate><enddate>200410</enddate><creator>Ferro, Albert</creator><creator>Coash, Marcy</creator><creator>Yamamoto, Takahiro</creator><creator>Rob, Jubli</creator><creator>Ji, Yong</creator><creator>Queen, Lindsay</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>200410</creationdate><title>Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt</title><author>Ferro, Albert ; Coash, Marcy ; Yamamoto, Takahiro ; Rob, Jubli ; Ji, Yong ; Queen, Lindsay</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p547-9bc96ddb3c08844040a1e49e4eb544e3ab0002163400b0237b54dce2eb3dd2983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adrenergic beta-2 Receptor Agonists</topic><topic>Adrenergic beta-Agonists - pharmacology</topic><topic>Adrenergic beta-Antagonists - pharmacology</topic><topic>Albuterol - pharmacology</topic><topic>Androstadienes - pharmacology</topic><topic>Animals</topic><topic>Aorta, Thoracic - drug effects</topic><topic>Aorta, Thoracic - physiology</topic><topic>Blotting, Western</topic><topic>Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>In Vitro Techniques</topic><topic>Isoproterenol - pharmacology</topic><topic>Isoquinolines - pharmacology</topic><topic>Male</topic><topic>NG-Nitroarginine Methyl Ester - pharmacology</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Synthase - antagonists & inhibitors</topic><topic>Nitric Oxide Synthase - metabolism</topic><topic>Phenylephrine - pharmacology</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Propanolamines - pharmacology</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptors, Adrenergic, beta-2 - physiology</topic><topic>Sulfonamides - pharmacology</topic><topic>Vasodilation - drug effects</topic><topic>Vasodilation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferro, Albert</creatorcontrib><creatorcontrib>Coash, Marcy</creatorcontrib><creatorcontrib>Yamamoto, Takahiro</creatorcontrib><creatorcontrib>Rob, Jubli</creatorcontrib><creatorcontrib>Ji, Yong</creatorcontrib><creatorcontrib>Queen, Lindsay</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferro, Albert</au><au>Coash, Marcy</au><au>Yamamoto, Takahiro</au><au>Rob, Jubli</au><au>Ji, Yong</au><au>Queen, Lindsay</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2004-10</date><risdate>2004</risdate><volume>143</volume><issue>3</issue><spage>397</spage><epage>403</epage><pages>397-403</pages><issn>0007-1188</issn><abstract>Vasorelaxation to beta(2)-adrenoceptor stimulation occurs through both endothelium-dependent and endothelium-independent mechanisms, and the former is mediated through Ca(2+)-independent activation of endothelial-type nitric oxide synthase (NOS-3). Since Ca(2+)-independent NOS-3 activation may occur through its serine phosphorylation via protein kinase A (PKA) or Akt, we determined the PKA and Akt dependency of beta(2)-adrenergic relaxation of rat aorta. Rat aortic rings were pre-incubated with the PKA inhibitor H-89 (10(-7) m), the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (5 x 10(-7) m), Akt inhibitor (10(-5) m), or vehicle, in the absence or presence of the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 10(-4) m). Rings were then contracted with phenylephrine (10(-7) m), and concentration-relaxation responses determined to the beta(2)-adrenoceptor agonist albuterol. Rings exhibited a concentration-dependent relaxation to albuterol: pEC(50) 6.9+/-0.2, E(max) 88.2+/-4.0%. l-NAME attenuated E(max) to 60.2+/-3.5% (P<0.001). In the presence of l-NAME, wortmannin or Akt inhibitor did not influence albuterol responses, whereas H-89 reduced E(max) further, to 27.5+/-2.2% (P<0.001). In the absence of l-NAME, E(max) to albuterol was reduced by H-89, wortmannin or Akt inhibitor, to 56.2+/-2.2, 56.0+/-1.6 and 55.4+/-1.8%, respectively (P<0.001 for each); the combinations H-89 plus wortmannin or H-89 plus Akt inhibitor reduced E(max) further still. Western blotting of NOS-3 immunoprecipitates from rat aortas confirmed that albuterol increased serine phosphorylation of NOS-3, and this increase was attenuated by H-89 or Akt inhibitor. Our results indicate that beta(2)-adrenoceptor stimulation relaxes rat aorta through both NO-dependent and independent mechanisms. The latter is predominantly PKA-mediated, whereas the former occurs through both PKA and PI3K/Akt activation.</abstract><cop>England</cop><pmid>15351777</pmid><tpages>7</tpages></addata></record> |
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| subjects | Adrenergic beta-2 Receptor Agonists Adrenergic beta-Agonists - pharmacology Adrenergic beta-Antagonists - pharmacology Albuterol - pharmacology Androstadienes - pharmacology Animals Aorta, Thoracic - drug effects Aorta, Thoracic - physiology Blotting, Western Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors Cyclic AMP-Dependent Protein Kinases - metabolism Dose-Response Relationship, Drug Enzyme Activation - drug effects Enzyme Inhibitors - pharmacology In Vitro Techniques Isoproterenol - pharmacology Isoquinolines - pharmacology Male NG-Nitroarginine Methyl Ester - pharmacology Nitric Oxide - metabolism Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - metabolism Phenylephrine - pharmacology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Propanolamines - pharmacology Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Rats Rats, Wistar Receptors, Adrenergic, beta-2 - physiology Sulfonamides - pharmacology Vasodilation - drug effects Vasodilation - physiology |
| title | Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt |
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