Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension
1 Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois 60611-3008; and 2 Department of Pediatrics and 3 Cardiothoracic Surgery, University of California, San Francisco, California 94143-0106 Life-threatening increases in pulmonary vascular resistance have been noted...
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| Veröffentlicht in: | American journal of physiology. Heart and circulatory physiology 1999-11, Vol.277 (5), p.H1849-H1856 |
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| container_issue | 5 |
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| container_title | American journal of physiology. Heart and circulatory physiology |
| container_volume | 277 |
| creator | Black, Stephen M Heidersbach, R. Scott McMullan, D. Michael Bekker, Janine M Johengen, Michael J Fineman, Jeffrey R |
| description | 1 Department of Pediatrics,
Northwestern University Medical School, Chicago, Illinois 60611-3008;
and 2 Department of Pediatrics and
3 Cardiothoracic Surgery,
University of California, San Francisco, California 94143-0106
Life-threatening increases in pulmonary
vascular resistance have been noted on acute withdrawal of inhaled
nitric oxide (NO), although the mechanisms remain unknown. In vitro
data suggest that exogenous NO exposure inhibits endothelial NO
synthase (NOS) activity. Thus the objectives of this study were to
determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb.
Six 1-mo-old lambs were mechanically ventilated and instrumented to
measure vascular pressures and left pulmonary blood flow. Inhaled NO
(40 ppm) acutely decreased left pulmonary vascular resistance by 27.5 ± 4.7% ( P |
| doi_str_mv | 10.1152/ajpheart.1999.277.5.h1849 |
| format | Article |
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Northwestern University Medical School, Chicago, Illinois 60611-3008;
and 2 Department of Pediatrics and
3 Cardiothoracic Surgery,
University of California, San Francisco, California 94143-0106
Life-threatening increases in pulmonary
vascular resistance have been noted on acute withdrawal of inhaled
nitric oxide (NO), although the mechanisms remain unknown. In vitro
data suggest that exogenous NO exposure inhibits endothelial NO
synthase (NOS) activity. Thus the objectives of this study were to
determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb.
Six 1-mo-old lambs were mechanically ventilated and instrumented to
measure vascular pressures and left pulmonary blood flow. Inhaled NO
(40 ppm) acutely decreased left pulmonary vascular resistance by 27.5 ± 4.7% ( P < 0.05).
This was associated with a 207% increase in plasma cGMP concentrations
( P < 0.05). After 6 h of inhaled NO,
NOS activity was reduced to 44.3 ± 5.9% of pre-NO values
( P < 0.05). After acute withdrawal
of NO, pulmonary vascular resistance increased by 52.1 ± 11.6%
( P < 0.05) and cGMP concentrations
decreased. Both returned to pre-NO values within 60 min. One hour after
NO withdrawal, NOS activity increased by 48.4 ± 19.1% to 70% of
pre-NO values ( P < 0.05).
Western blot analysis revealed that endothelial NOS protein levels
remained unchanged throughout the study period. These data suggest a
role for decreased endogenous NOS activity in the rebound pulmonary
hypertension noted after acute withdrawal of inhaled NO.
endothelium-derived factors; pulmonary heart disease</description><identifier>ISSN: 0363-6135</identifier><identifier>ISSN: 0002-9513</identifier><identifier>EISSN: 1522-1539</identifier><identifier>DOI: 10.1152/ajpheart.1999.277.5.h1849</identifier><identifier>PMID: 10564139</identifier><language>eng</language><publisher>United States</publisher><subject>Administration, Inhalation ; Animals ; Cyclic GMP - blood ; Endothelium, Vascular - enzymology ; Enzyme Inhibitors - administration & dosage ; Enzyme Inhibitors - adverse effects ; Enzyme Inhibitors - pharmacology ; Gene Expression - drug effects ; Hypertension, Pulmonary - chemically induced ; Nitric Oxide - administration & dosage ; Nitric Oxide - adverse effects ; Nitric Oxide - pharmacology ; Nitric Oxide Synthase - antagonists & inhibitors ; Nitric Oxide Synthase - genetics ; Nitric Oxide Synthase - metabolism ; Pulmonary Circulation - drug effects ; Sheep ; Substance Withdrawal Syndrome ; Time Factors ; Vascular Resistance - drug effects</subject><ispartof>American journal of physiology. Heart and circulatory physiology, 1999-11, Vol.277 (5), p.H1849-H1856</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-f7ea83a79f8d49d921f2a58d4cf5407bfb89cdff990d386cf90870d22c9c44b23</citedby><cites>FETCH-LOGICAL-c471t-f7ea83a79f8d49d921f2a58d4cf5407bfb89cdff990d386cf90870d22c9c44b23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,3026,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10564139$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Black, Stephen M</creatorcontrib><creatorcontrib>Heidersbach, R. Scott</creatorcontrib><creatorcontrib>McMullan, D. Michael</creatorcontrib><creatorcontrib>Bekker, Janine M</creatorcontrib><creatorcontrib>Johengen, Michael J</creatorcontrib><creatorcontrib>Fineman, Jeffrey R</creatorcontrib><title>Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension</title><title>American journal of physiology. Heart and circulatory physiology</title><addtitle>Am J Physiol</addtitle><description>1 Department of Pediatrics,
Northwestern University Medical School, Chicago, Illinois 60611-3008;
and 2 Department of Pediatrics and
3 Cardiothoracic Surgery,
University of California, San Francisco, California 94143-0106
Life-threatening increases in pulmonary
vascular resistance have been noted on acute withdrawal of inhaled
nitric oxide (NO), although the mechanisms remain unknown. In vitro
data suggest that exogenous NO exposure inhibits endothelial NO
synthase (NOS) activity. Thus the objectives of this study were to
determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb.
Six 1-mo-old lambs were mechanically ventilated and instrumented to
measure vascular pressures and left pulmonary blood flow. Inhaled NO
(40 ppm) acutely decreased left pulmonary vascular resistance by 27.5 ± 4.7% ( P < 0.05).
This was associated with a 207% increase in plasma cGMP concentrations
( P < 0.05). After 6 h of inhaled NO,
NOS activity was reduced to 44.3 ± 5.9% of pre-NO values
( P < 0.05). After acute withdrawal
of NO, pulmonary vascular resistance increased by 52.1 ± 11.6%
( P < 0.05) and cGMP concentrations
decreased. Both returned to pre-NO values within 60 min. One hour after
NO withdrawal, NOS activity increased by 48.4 ± 19.1% to 70% of
pre-NO values ( P < 0.05).
Western blot analysis revealed that endothelial NOS protein levels
remained unchanged throughout the study period. These data suggest a
role for decreased endogenous NOS activity in the rebound pulmonary
hypertension noted after acute withdrawal of inhaled NO.
endothelium-derived factors; pulmonary heart disease</description><subject>Administration, Inhalation</subject><subject>Animals</subject><subject>Cyclic GMP - blood</subject><subject>Endothelium, Vascular - enzymology</subject><subject>Enzyme Inhibitors - administration & dosage</subject><subject>Enzyme Inhibitors - adverse effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene Expression - drug effects</subject><subject>Hypertension, Pulmonary - chemically induced</subject><subject>Nitric Oxide - administration & dosage</subject><subject>Nitric Oxide - adverse effects</subject><subject>Nitric Oxide - pharmacology</subject><subject>Nitric Oxide Synthase - antagonists & inhibitors</subject><subject>Nitric Oxide Synthase - genetics</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Pulmonary Circulation - drug effects</subject><subject>Sheep</subject><subject>Substance Withdrawal Syndrome</subject><subject>Time Factors</subject><subject>Vascular Resistance - drug effects</subject><issn>0363-6135</issn><issn>0002-9513</issn><issn>1522-1539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMlO9SAYhonR6HG4BYMX0AqltOV3ZYxTYnShrgllEPw7BThq715OjuPCFV_43ucNPAAcYZRjTItj8TxZLXzMMWMsL-o6p7nFTck2wCLtiwxTwjbBApGKZBUmdAfshvCMEKJ1RbbBDka0KjFhC_D_erCi0woOLnon4fjmlIZusK51McDbu3soZHQvLs7pFnaib8M_OI1RD9GJDvZaWjG40EMzeuh1Oy4HBadl14-D8DO086R9Cgc3Dvtgy4gu6IOPcw88Xpw_nF1lN3eX12enN5ksaxwzU2vREFEz06iSKVZgUwiaZmloierWtA2TyhjGkCJNJQ1DTY1UUUgmy7ItyB5g617pxxC8Nnzyrk-v4RjxlUD-KZCvBPIkkFN-tRKY2MM1Oy3bXqsf5NpYChyvA9Y92VfnNZ_snH7XjU_zd-_vypO_iYtl1z3ot_iF_iD5pAx5B_vfmQM</recordid><startdate>19991101</startdate><enddate>19991101</enddate><creator>Black, Stephen M</creator><creator>Heidersbach, R. Scott</creator><creator>McMullan, D. Michael</creator><creator>Bekker, Janine M</creator><creator>Johengen, Michael J</creator><creator>Fineman, Jeffrey R</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>19991101</creationdate><title>Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension</title><author>Black, Stephen M ; Heidersbach, R. Scott ; McMullan, D. Michael ; Bekker, Janine M ; Johengen, Michael J ; Fineman, Jeffrey R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c471t-f7ea83a79f8d49d921f2a58d4cf5407bfb89cdff990d386cf90870d22c9c44b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Administration, Inhalation</topic><topic>Animals</topic><topic>Cyclic GMP - blood</topic><topic>Endothelium, Vascular - enzymology</topic><topic>Enzyme Inhibitors - administration & dosage</topic><topic>Enzyme Inhibitors - adverse effects</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene Expression - drug effects</topic><topic>Hypertension, Pulmonary - chemically induced</topic><topic>Nitric Oxide - administration & dosage</topic><topic>Nitric Oxide - adverse effects</topic><topic>Nitric Oxide - pharmacology</topic><topic>Nitric Oxide Synthase - antagonists & inhibitors</topic><topic>Nitric Oxide Synthase - genetics</topic><topic>Nitric Oxide Synthase - metabolism</topic><topic>Pulmonary Circulation - drug effects</topic><topic>Sheep</topic><topic>Substance Withdrawal Syndrome</topic><topic>Time Factors</topic><topic>Vascular Resistance - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Black, Stephen M</creatorcontrib><creatorcontrib>Heidersbach, R. Scott</creatorcontrib><creatorcontrib>McMullan, D. Michael</creatorcontrib><creatorcontrib>Bekker, Janine M</creatorcontrib><creatorcontrib>Johengen, Michael J</creatorcontrib><creatorcontrib>Fineman, Jeffrey R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Black, Stephen M</au><au>Heidersbach, R. Scott</au><au>McMullan, D. Michael</au><au>Bekker, Janine M</au><au>Johengen, Michael J</au><au>Fineman, Jeffrey R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension</atitle><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle><addtitle>Am J Physiol</addtitle><date>1999-11-01</date><risdate>1999</risdate><volume>277</volume><issue>5</issue><spage>H1849</spage><epage>H1856</epage><pages>H1849-H1856</pages><issn>0363-6135</issn><issn>0002-9513</issn><eissn>1522-1539</eissn><abstract>1 Department of Pediatrics,
Northwestern University Medical School, Chicago, Illinois 60611-3008;
and 2 Department of Pediatrics and
3 Cardiothoracic Surgery,
University of California, San Francisco, California 94143-0106
Life-threatening increases in pulmonary
vascular resistance have been noted on acute withdrawal of inhaled
nitric oxide (NO), although the mechanisms remain unknown. In vitro
data suggest that exogenous NO exposure inhibits endothelial NO
synthase (NOS) activity. Thus the objectives of this study were to
determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb.
Six 1-mo-old lambs were mechanically ventilated and instrumented to
measure vascular pressures and left pulmonary blood flow. Inhaled NO
(40 ppm) acutely decreased left pulmonary vascular resistance by 27.5 ± 4.7% ( P < 0.05).
This was associated with a 207% increase in plasma cGMP concentrations
( P < 0.05). After 6 h of inhaled NO,
NOS activity was reduced to 44.3 ± 5.9% of pre-NO values
( P < 0.05). After acute withdrawal
of NO, pulmonary vascular resistance increased by 52.1 ± 11.6%
( P < 0.05) and cGMP concentrations
decreased. Both returned to pre-NO values within 60 min. One hour after
NO withdrawal, NOS activity increased by 48.4 ± 19.1% to 70% of
pre-NO values ( P < 0.05).
Western blot analysis revealed that endothelial NOS protein levels
remained unchanged throughout the study period. These data suggest a
role for decreased endogenous NOS activity in the rebound pulmonary
hypertension noted after acute withdrawal of inhaled NO.
endothelium-derived factors; pulmonary heart disease</abstract><cop>United States</cop><pmid>10564139</pmid><doi>10.1152/ajpheart.1999.277.5.h1849</doi></addata></record> |
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| ispartof | American journal of physiology. Heart and circulatory physiology, 1999-11, Vol.277 (5), p.H1849-H1856 |
| issn | 0363-6135 0002-9513 1522-1539 |
| language | eng |
| recordid | cdi_highwire_physiology_ajpheart_277_5_H1849 |
| source | MEDLINE; American Physiological Society; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Administration, Inhalation Animals Cyclic GMP - blood Endothelium, Vascular - enzymology Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - adverse effects Enzyme Inhibitors - pharmacology Gene Expression - drug effects Hypertension, Pulmonary - chemically induced Nitric Oxide - administration & dosage Nitric Oxide - adverse effects Nitric Oxide - pharmacology Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - genetics Nitric Oxide Synthase - metabolism Pulmonary Circulation - drug effects Sheep Substance Withdrawal Syndrome Time Factors Vascular Resistance - drug effects |
| title | Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension |
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