Milrinone relaxes pulmonary veins in guinea pigs and humans
The phosphodiesterase-III inhibitor milrinone improves ventricular contractility, relaxes pulmonary arteries and reduces right ventricular afterload. Thus, it is used to treat heart failure and pulmonary hypertension (PH). However, its action on pulmonary veins (PVs) is not defined, although particu...
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| creator | Rieg, Annette D Suleiman, Said Perez-Bouza, Alberto Braunschweig, Till Spillner, Jan W Schröder, Thomas Verjans, Eva Schälte, Gereon Rossaint, Rolf Uhlig, Stefan Martin, Christian |
| description | The phosphodiesterase-III inhibitor milrinone improves ventricular contractility, relaxes pulmonary arteries and reduces right ventricular afterload. Thus, it is used to treat heart failure and pulmonary hypertension (PH). However, its action on pulmonary veins (PVs) is not defined, although particularly PH due to left heart disease primarily affects the pulmonary venous bed. We examined milrinone-induced relaxation in PVs from guinea pigs (GPs) and humans.
Precision-cut lung slices (PCLS) were prepared from GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was studied by videomicroscopy in naïve PVs and in PVs pre-constricted with the ETA-receptor agonist BP0104. Baseline luminal area was defined as 100%. Intracellular cAMP was measured by ELISA and milrinone-induced changes of segmental vascular resistances were studied in the GP isolated perfused lung (IPL).
In the IPL (GP), milrinone (10 µM) lowered the postcapillary resistance of pre-constricted vessels. In PCLS (GP), milrinone relaxed naïve and pre-constricted PVs (120%) and this relaxation was attenuated by inhibition of protein kinase G (KT 5823), adenyl cyclase (SQ 22536) and protein kinase A (KT 5720), but not by inhibition of NO-synthesis (L-NAME). In addition, milrinone-induced relaxation was dependent on the activation of K ATP-, BK Ca (2+)- and Kv-channels. Human PVs also relaxed to milrinone (121%), however only if pre-constricted.
Milrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on K ATP-, BK Ca (2+)- and Kv-channel-activation and on cAMP/PKA/PKG. The relaxant properties of milrinone on PVs lead to reduced postcapillary resistance and hydrostatic pressures. Hence they alleviate pulmonary edema and suggest beneficial effects of milrinone in PH due to left heart disease. |
| doi_str_mv | 10.1371/journal.pone.0087685 |
| format | Article |
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Precision-cut lung slices (PCLS) were prepared from GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was studied by videomicroscopy in naïve PVs and in PVs pre-constricted with the ETA-receptor agonist BP0104. Baseline luminal area was defined as 100%. Intracellular cAMP was measured by ELISA and milrinone-induced changes of segmental vascular resistances were studied in the GP isolated perfused lung (IPL).
In the IPL (GP), milrinone (10 µM) lowered the postcapillary resistance of pre-constricted vessels. In PCLS (GP), milrinone relaxed naïve and pre-constricted PVs (120%) and this relaxation was attenuated by inhibition of protein kinase G (KT 5823), adenyl cyclase (SQ 22536) and protein kinase A (KT 5720), but not by inhibition of NO-synthesis (L-NAME). In addition, milrinone-induced relaxation was dependent on the activation of K ATP-, BK Ca (2+)- and Kv-channels. Human PVs also relaxed to milrinone (121%), however only if pre-constricted.
Milrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on K ATP-, BK Ca (2+)- and Kv-channel-activation and on cAMP/PKA/PKG. The relaxant properties of milrinone on PVs lead to reduced postcapillary resistance and hydrostatic pressures. Hence they alleviate pulmonary edema and suggest beneficial effects of milrinone in PH due to left heart disease.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0087685</identifier><identifier>PMID: 24498166</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Anesthesiology ; Animals ; Arteries ; Biology ; Blood vessels ; Cardiovascular disease ; Constrictions ; Coronary artery disease ; Coronary vessels ; Cyclic adenosine monophosphate ; Cyclic AMP ; Edema ; Enzyme-linked immunosorbent assay ; Female ; Guinea Pigs ; Heart ; Heart diseases ; Heart failure ; Humans ; Hypertension ; Hypoxia ; Inhibition ; Large-Conductance Calcium-Activated Potassium Channels - metabolism ; Lung diseases ; Lungs ; Male ; Mathematics ; Medical research ; Medicine ; Milrinone ; Milrinone - pharmacology ; Muscle contraction ; NG-Nitroarginine methyl ester ; Nitric oxide ; Organ Culture Techniques ; Pathology ; Pharmacology ; Phosphodiesterase ; Phosphodiesterase 3 Inhibitors - pharmacology ; Potassium ; Protein kinase A ; Protein kinase G ; Pulmonary arteries ; Pulmonary artery ; Pulmonary Edema - drug therapy ; Pulmonary Edema - metabolism ; Pulmonary Edema - pathology ; Pulmonary Edema - physiopathology ; Pulmonary hypertension ; Pulmonary Veins - metabolism ; Pulmonary Veins - pathology ; Pulmonary Veins - physiopathology ; Smooth muscle ; Surgery ; Toxicology ; Vascular Resistance - drug effects ; Vasodilation - drug effects ; Veins ; Veins & arteries ; Ventricle</subject><ispartof>PloS one, 2014-01, Vol.9 (1), p.e87685</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Rieg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Rieg et al 2014 Rieg et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-ab784691836904d00efd29698f871f580bf2cf51f7567844135100414e3d48fb3</citedby><cites>FETCH-LOGICAL-c692t-ab784691836904d00efd29698f871f580bf2cf51f7567844135100414e3d48fb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909212/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909212/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24498166$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bauer, Philip Michael</contributor><creatorcontrib>Rieg, Annette D</creatorcontrib><creatorcontrib>Suleiman, Said</creatorcontrib><creatorcontrib>Perez-Bouza, Alberto</creatorcontrib><creatorcontrib>Braunschweig, Till</creatorcontrib><creatorcontrib>Spillner, Jan W</creatorcontrib><creatorcontrib>Schröder, Thomas</creatorcontrib><creatorcontrib>Verjans, Eva</creatorcontrib><creatorcontrib>Schälte, Gereon</creatorcontrib><creatorcontrib>Rossaint, Rolf</creatorcontrib><creatorcontrib>Uhlig, Stefan</creatorcontrib><creatorcontrib>Martin, Christian</creatorcontrib><title>Milrinone relaxes pulmonary veins in guinea pigs and humans</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The phosphodiesterase-III inhibitor milrinone improves ventricular contractility, relaxes pulmonary arteries and reduces right ventricular afterload. Thus, it is used to treat heart failure and pulmonary hypertension (PH). However, its action on pulmonary veins (PVs) is not defined, although particularly PH due to left heart disease primarily affects the pulmonary venous bed. We examined milrinone-induced relaxation in PVs from guinea pigs (GPs) and humans.
Precision-cut lung slices (PCLS) were prepared from GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was studied by videomicroscopy in naïve PVs and in PVs pre-constricted with the ETA-receptor agonist BP0104. Baseline luminal area was defined as 100%. Intracellular cAMP was measured by ELISA and milrinone-induced changes of segmental vascular resistances were studied in the GP isolated perfused lung (IPL).
In the IPL (GP), milrinone (10 µM) lowered the postcapillary resistance of pre-constricted vessels. In PCLS (GP), milrinone relaxed naïve and pre-constricted PVs (120%) and this relaxation was attenuated by inhibition of protein kinase G (KT 5823), adenyl cyclase (SQ 22536) and protein kinase A (KT 5720), but not by inhibition of NO-synthesis (L-NAME). In addition, milrinone-induced relaxation was dependent on the activation of K ATP-, BK Ca (2+)- and Kv-channels. Human PVs also relaxed to milrinone (121%), however only if pre-constricted.
Milrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on K ATP-, BK Ca (2+)- and Kv-channel-activation and on cAMP/PKA/PKG. The relaxant properties of milrinone on PVs lead to reduced postcapillary resistance and hydrostatic pressures. Hence they alleviate pulmonary edema and suggest beneficial effects of milrinone in PH due to left heart disease.</description><subject>Activation</subject><subject>Anesthesiology</subject><subject>Animals</subject><subject>Arteries</subject><subject>Biology</subject><subject>Blood vessels</subject><subject>Cardiovascular disease</subject><subject>Constrictions</subject><subject>Coronary artery disease</subject><subject>Coronary vessels</subject><subject>Cyclic adenosine monophosphate</subject><subject>Cyclic AMP</subject><subject>Edema</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Female</subject><subject>Guinea Pigs</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Hypoxia</subject><subject>Inhibition</subject><subject>Large-Conductance Calcium-Activated Potassium Channels - metabolism</subject><subject>Lung diseases</subject><subject>Lungs</subject><subject>Male</subject><subject>Mathematics</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Milrinone</subject><subject>Milrinone - pharmacology</subject><subject>Muscle contraction</subject><subject>NG-Nitroarginine methyl ester</subject><subject>Nitric oxide</subject><subject>Organ Culture Techniques</subject><subject>Pathology</subject><subject>Pharmacology</subject><subject>Phosphodiesterase</subject><subject>Phosphodiesterase 3 Inhibitors - pharmacology</subject><subject>Potassium</subject><subject>Protein kinase A</subject><subject>Protein kinase G</subject><subject>Pulmonary arteries</subject><subject>Pulmonary artery</subject><subject>Pulmonary Edema - drug therapy</subject><subject>Pulmonary Edema - metabolism</subject><subject>Pulmonary Edema - pathology</subject><subject>Pulmonary Edema - physiopathology</subject><subject>Pulmonary hypertension</subject><subject>Pulmonary Veins - metabolism</subject><subject>Pulmonary Veins - pathology</subject><subject>Pulmonary Veins - physiopathology</subject><subject>Smooth muscle</subject><subject>Surgery</subject><subject>Toxicology</subject><subject>Vascular Resistance - drug effects</subject><subject>Vasodilation - drug effects</subject><subject>Veins</subject><subject>Veins & arteries</subject><subject>Ventricle</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkmuL1DAUhoso7rr6D0QLguCHGXNrkiIIy-JlYGXB29eQtiedDG3STdpl_fdmnO4yBQXJh4ST57x5z8nJsucYrTEV-O3OT8Hpbj14B2uEpOCyeJCd4pKSFSeIPjw6n2RPYtwhVFDJ-ePshDBWSsz5afbui-2CdUkjD9DpW4j5MHW9dzr8ym_Auphbl7eTdaDzwbYx167Jt1OvXXyaPTK6i_Bs3s-yHx8_fL_4vLq8-rS5OL9c1bwk40pXQjJeYkl5iViDEJiGlLyURgpsCokqQ2pTYCMKnkiGaYERYpgBbZg0FT3LXh50h85HNdcdFS6FSHWQgiVicyAar3dqCLZP9pXXVv0J-NAqHUZbd6AqQkQjheACgIGEyuztFRXhlaQNhqT1fn5tqnpoanBj0N1CdHnj7Fa1_kbREpUEkyTwahYI_nqCOP7D8ky1OrmyzvgkVvc21uqcCSkpIWhPrf9CpdVAb-v0a8am-CLhzSIhMSPcjq2eYlSbb1__n736uWRfH7Fb0N24jb6bRutdXILsANbBxxjA3HcOI7Uf3LtuqP3gqnlwU9qL467fJ91NKv0NtqXmxA</recordid><startdate>20140131</startdate><enddate>20140131</enddate><creator>Rieg, Annette D</creator><creator>Suleiman, Said</creator><creator>Perez-Bouza, Alberto</creator><creator>Braunschweig, Till</creator><creator>Spillner, Jan W</creator><creator>Schröder, Thomas</creator><creator>Verjans, Eva</creator><creator>Schälte, Gereon</creator><creator>Rossaint, Rolf</creator><creator>Uhlig, Stefan</creator><creator>Martin, Christian</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140131</creationdate><title>Milrinone relaxes pulmonary veins in guinea pigs and humans</title><author>Rieg, Annette D ; Suleiman, Said ; Perez-Bouza, Alberto ; Braunschweig, Till ; Spillner, Jan W ; Schröder, Thomas ; Verjans, Eva ; Schälte, Gereon ; Rossaint, Rolf ; Uhlig, Stefan ; Martin, Christian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-ab784691836904d00efd29698f871f580bf2cf51f7567844135100414e3d48fb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Activation</topic><topic>Anesthesiology</topic><topic>Animals</topic><topic>Arteries</topic><topic>Biology</topic><topic>Blood vessels</topic><topic>Cardiovascular disease</topic><topic>Constrictions</topic><topic>Coronary artery disease</topic><topic>Coronary vessels</topic><topic>Cyclic adenosine monophosphate</topic><topic>Cyclic AMP</topic><topic>Edema</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Female</topic><topic>Guinea Pigs</topic><topic>Heart</topic><topic>Heart diseases</topic><topic>Heart failure</topic><topic>Humans</topic><topic>Hypertension</topic><topic>Hypoxia</topic><topic>Inhibition</topic><topic>Large-Conductance Calcium-Activated Potassium Channels - metabolism</topic><topic>Lung diseases</topic><topic>Lungs</topic><topic>Male</topic><topic>Mathematics</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Milrinone</topic><topic>Milrinone - pharmacology</topic><topic>Muscle contraction</topic><topic>NG-Nitroarginine methyl ester</topic><topic>Nitric oxide</topic><topic>Organ Culture Techniques</topic><topic>Pathology</topic><topic>Pharmacology</topic><topic>Phosphodiesterase</topic><topic>Phosphodiesterase 3 Inhibitors - pharmacology</topic><topic>Potassium</topic><topic>Protein kinase A</topic><topic>Protein kinase G</topic><topic>Pulmonary arteries</topic><topic>Pulmonary artery</topic><topic>Pulmonary Edema - drug therapy</topic><topic>Pulmonary Edema - metabolism</topic><topic>Pulmonary Edema - pathology</topic><topic>Pulmonary Edema - physiopathology</topic><topic>Pulmonary hypertension</topic><topic>Pulmonary Veins - metabolism</topic><topic>Pulmonary Veins - pathology</topic><topic>Pulmonary Veins - physiopathology</topic><topic>Smooth muscle</topic><topic>Surgery</topic><topic>Toxicology</topic><topic>Vascular Resistance - 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Thus, it is used to treat heart failure and pulmonary hypertension (PH). However, its action on pulmonary veins (PVs) is not defined, although particularly PH due to left heart disease primarily affects the pulmonary venous bed. We examined milrinone-induced relaxation in PVs from guinea pigs (GPs) and humans.
Precision-cut lung slices (PCLS) were prepared from GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was studied by videomicroscopy in naïve PVs and in PVs pre-constricted with the ETA-receptor agonist BP0104. Baseline luminal area was defined as 100%. Intracellular cAMP was measured by ELISA and milrinone-induced changes of segmental vascular resistances were studied in the GP isolated perfused lung (IPL).
In the IPL (GP), milrinone (10 µM) lowered the postcapillary resistance of pre-constricted vessels. In PCLS (GP), milrinone relaxed naïve and pre-constricted PVs (120%) and this relaxation was attenuated by inhibition of protein kinase G (KT 5823), adenyl cyclase (SQ 22536) and protein kinase A (KT 5720), but not by inhibition of NO-synthesis (L-NAME). In addition, milrinone-induced relaxation was dependent on the activation of K ATP-, BK Ca (2+)- and Kv-channels. Human PVs also relaxed to milrinone (121%), however only if pre-constricted.
Milrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on K ATP-, BK Ca (2+)- and Kv-channel-activation and on cAMP/PKA/PKG. The relaxant properties of milrinone on PVs lead to reduced postcapillary resistance and hydrostatic pressures. Hence they alleviate pulmonary edema and suggest beneficial effects of milrinone in PH due to left heart disease.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24498166</pmid><doi>10.1371/journal.pone.0087685</doi><tpages>e87685</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-01, Vol.9 (1), p.e87685 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1977449254 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Anesthesiology Animals Arteries Biology Blood vessels Cardiovascular disease Constrictions Coronary artery disease Coronary vessels Cyclic adenosine monophosphate Cyclic AMP Edema Enzyme-linked immunosorbent assay Female Guinea Pigs Heart Heart diseases Heart failure Humans Hypertension Hypoxia Inhibition Large-Conductance Calcium-Activated Potassium Channels - metabolism Lung diseases Lungs Male Mathematics Medical research Medicine Milrinone Milrinone - pharmacology Muscle contraction NG-Nitroarginine methyl ester Nitric oxide Organ Culture Techniques Pathology Pharmacology Phosphodiesterase Phosphodiesterase 3 Inhibitors - pharmacology Potassium Protein kinase A Protein kinase G Pulmonary arteries Pulmonary artery Pulmonary Edema - drug therapy Pulmonary Edema - metabolism Pulmonary Edema - pathology Pulmonary Edema - physiopathology Pulmonary hypertension Pulmonary Veins - metabolism Pulmonary Veins - pathology Pulmonary Veins - physiopathology Smooth muscle Surgery Toxicology Vascular Resistance - drug effects Vasodilation - drug effects Veins Veins & arteries Ventricle |
| title | Milrinone relaxes pulmonary veins in guinea pigs and humans |
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