Calcium dynamics in the failing heart: restoration by {beta}-adrenergic receptor blockade
Divisions of 1 Molecular Cardiovascular Biology and 2 Cardiology, The Children's Hospital and Research Foundation, Cincinnati 45229; 3 Department of Physiology and Cell Biology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210; 4 Cardiovascular Research Ins...
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| Veröffentlicht in: | American journal of physiology. Heart and circulatory physiology 2003-06, Vol.285 (1), p.H305 |
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| container_title | American journal of physiology. Heart and circulatory physiology |
| container_volume | 285 |
| creator | Plank, David M Yatani, Atsuko Ritsu, Honda Witt, Sandra Glascock, Betty Lalli, M. Jane Periasamy, Muthu Fiset, Celine Benkusky, Nancy Valdivia, Hector H Sussman, Mark A |
| description | Divisions of 1 Molecular Cardiovascular Biology
and 2 Cardiology, The Children's Hospital and Research
Foundation, Cincinnati 45229; 3 Department of
Physiology and Cell Biology, College of Medicine and Public Health, The Ohio
State University, Columbus, Ohio 43210;
4 Cardiovascular Research Institute and Department of
Medicine, New Jersey Medical School, University of Medicine and Dentistry of
New Jersey, Newark, New Jersey 07103; 5 Department of
Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706;
and 6 Research Center, Montreal Heart Institute,
Montreal, Quebec, Canada H1T 1C8
Submitted 20 May 2002
; accepted in final form 11 March 2003
Changes in calcium (Ca 2+ ) regulation contribute to loss of
contractile function in dilated cardiomyopathy. Clinical treatment using
-adrenergic receptor antagonists ( -blockers) slows deterioration
of cardiac function in end-stage heart failure patients; however, the effects
of -blocker treatment on Ca 2+ dynamics in the failing heart
are unknown. To address this issue, tropomodulin-overexpressing transgenic
(TOT) mice, which suffer from dilated cardiomyopathy, were treated with a
nonselective -receptor blocker (5 mg · kg -1 ·
day -1 propranolol) for 2 wk. Ca 2+ dynamics in isolated
cardiomyocytes of TOT mice significantly improved after treatment compared
with untreated TOT mice. Frequency-dependent diastolic and Ca 2+
transient amplitudes were returned to normal in propranolol-treated TOT mice
and but not in untreated TOT mice. Ca 2+ kinetic measurements of
time to peak and time decay of the caffeine-induced Ca 2+ transient
to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT
heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum
Ca 2+ -ATPase (SERCA), whereas Na + /Ca 2+
exchanger (NCX) concentrations were increased 2.6-fold relative to
nontransgenic samples. Propranolol treatment of TOT mice reversed the
alterations in SERCA and NCX protein levels but not potassium channels.
Although restoration of Ca 2+ dynamics occurred within 2 wk of
-blockade treatment, evidence of functional improvement in cardiac
contractility assessed by echocardiography took 10 wk to materialize. These
results demonstrate that -adrenergic blockade restores Ca 2+
dynamics and normalizes expression of Ca 2+ -handling proteins,
eventually leading to improved hemodynamic function in cardiomyopathic
hearts.
cardiomyopathy; -adrenergic receptor antagonists; dilated
Address for rep |
| doi_str_mv | 10.1152/ajpheart.00425.2002 |
| format | Article |
| fullrecord | <record><control><sourceid>highwire</sourceid><recordid>TN_cdi_highwire_physiology_ajpheart_285_1_H305</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>ajpheart_285_1_H305</sourcerecordid><originalsourceid>FETCH-highwire_physiology_ajpheart_285_1_H3053</originalsourceid><addsrcrecordid>eNqdj01OwzAUhC1URMPPCdj4AgnPdp3SbiuqHqAbVpbjvMQubhLZriBC3J0IFVixYTWL-T6NhpB7BgVjkj_ow2BRh1QALLgsOAC_INnU8JxJsZqRDEQp8pIJOSfXMR4AQC5LcUXmjJeLFSx5Rp432ht3OtJ67PTRmUhdR5NF2mjnXdfSr4k1DRhTH3RyfUerkb5XmPRHruuAHYbWmQkwOEwIrXxvXnSNt-Sy0T7i3TlvSLF92m92uXWtfXUB1WDH6Hrft6P6_qL4o1RM7QRI8Q9h_bewPXm_x7f0Y_6Kaqgb8QkONmvd</addsrcrecordid><sourcetype>Enrichment Source</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Calcium dynamics in the failing heart: restoration by {beta}-adrenergic receptor blockade</title><source>American Physiological Society</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Plank, David M ; Yatani, Atsuko ; Ritsu, Honda ; Witt, Sandra ; Glascock, Betty ; Lalli, M. Jane ; Periasamy, Muthu ; Fiset, Celine ; Benkusky, Nancy ; Valdivia, Hector H ; Sussman, Mark A</creator><creatorcontrib>Plank, David M ; Yatani, Atsuko ; Ritsu, Honda ; Witt, Sandra ; Glascock, Betty ; Lalli, M. Jane ; Periasamy, Muthu ; Fiset, Celine ; Benkusky, Nancy ; Valdivia, Hector H ; Sussman, Mark A</creatorcontrib><description>Divisions of 1 Molecular Cardiovascular Biology
and 2 Cardiology, The Children's Hospital and Research
Foundation, Cincinnati 45229; 3 Department of
Physiology and Cell Biology, College of Medicine and Public Health, The Ohio
State University, Columbus, Ohio 43210;
4 Cardiovascular Research Institute and Department of
Medicine, New Jersey Medical School, University of Medicine and Dentistry of
New Jersey, Newark, New Jersey 07103; 5 Department of
Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706;
and 6 Research Center, Montreal Heart Institute,
Montreal, Quebec, Canada H1T 1C8
Submitted 20 May 2002
; accepted in final form 11 March 2003
Changes in calcium (Ca 2+ ) regulation contribute to loss of
contractile function in dilated cardiomyopathy. Clinical treatment using
-adrenergic receptor antagonists ( -blockers) slows deterioration
of cardiac function in end-stage heart failure patients; however, the effects
of -blocker treatment on Ca 2+ dynamics in the failing heart
are unknown. To address this issue, tropomodulin-overexpressing transgenic
(TOT) mice, which suffer from dilated cardiomyopathy, were treated with a
nonselective -receptor blocker (5 mg · kg -1 ·
day -1 propranolol) for 2 wk. Ca 2+ dynamics in isolated
cardiomyocytes of TOT mice significantly improved after treatment compared
with untreated TOT mice. Frequency-dependent diastolic and Ca 2+
transient amplitudes were returned to normal in propranolol-treated TOT mice
and but not in untreated TOT mice. Ca 2+ kinetic measurements of
time to peak and time decay of the caffeine-induced Ca 2+ transient
to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT
heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum
Ca 2+ -ATPase (SERCA), whereas Na + /Ca 2+
exchanger (NCX) concentrations were increased 2.6-fold relative to
nontransgenic samples. Propranolol treatment of TOT mice reversed the
alterations in SERCA and NCX protein levels but not potassium channels.
Although restoration of Ca 2+ dynamics occurred within 2 wk of
-blockade treatment, evidence of functional improvement in cardiac
contractility assessed by echocardiography took 10 wk to materialize. These
results demonstrate that -adrenergic blockade restores Ca 2+
dynamics and normalizes expression of Ca 2+ -handling proteins,
eventually leading to improved hemodynamic function in cardiomyopathic
hearts.
cardiomyopathy; -adrenergic receptor antagonists; dilated
Address for reprint requests and other correspondence: M. A. Sussman, Div. of
Molecular and Cardiovascular Biology, Rm. 3033, The Children's Hospital and
Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229 (E-mail:
sussman{at}heart.chmcc.org ).</description><identifier>ISSN: 0363-6135</identifier><identifier>EISSN: 1522-1539</identifier><identifier>DOI: 10.1152/ajpheart.00425.2002</identifier><identifier>PMID: 12649072</identifier><language>eng</language><ispartof>American journal of physiology. Heart and circulatory physiology, 2003-06, Vol.285 (1), p.H305</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>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Plank, David M</creatorcontrib><creatorcontrib>Yatani, Atsuko</creatorcontrib><creatorcontrib>Ritsu, Honda</creatorcontrib><creatorcontrib>Witt, Sandra</creatorcontrib><creatorcontrib>Glascock, Betty</creatorcontrib><creatorcontrib>Lalli, M. Jane</creatorcontrib><creatorcontrib>Periasamy, Muthu</creatorcontrib><creatorcontrib>Fiset, Celine</creatorcontrib><creatorcontrib>Benkusky, Nancy</creatorcontrib><creatorcontrib>Valdivia, Hector H</creatorcontrib><creatorcontrib>Sussman, Mark A</creatorcontrib><title>Calcium dynamics in the failing heart: restoration by {beta}-adrenergic receptor blockade</title><title>American journal of physiology. Heart and circulatory physiology</title><description>Divisions of 1 Molecular Cardiovascular Biology
and 2 Cardiology, The Children's Hospital and Research
Foundation, Cincinnati 45229; 3 Department of
Physiology and Cell Biology, College of Medicine and Public Health, The Ohio
State University, Columbus, Ohio 43210;
4 Cardiovascular Research Institute and Department of
Medicine, New Jersey Medical School, University of Medicine and Dentistry of
New Jersey, Newark, New Jersey 07103; 5 Department of
Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706;
and 6 Research Center, Montreal Heart Institute,
Montreal, Quebec, Canada H1T 1C8
Submitted 20 May 2002
; accepted in final form 11 March 2003
Changes in calcium (Ca 2+ ) regulation contribute to loss of
contractile function in dilated cardiomyopathy. Clinical treatment using
-adrenergic receptor antagonists ( -blockers) slows deterioration
of cardiac function in end-stage heart failure patients; however, the effects
of -blocker treatment on Ca 2+ dynamics in the failing heart
are unknown. To address this issue, tropomodulin-overexpressing transgenic
(TOT) mice, which suffer from dilated cardiomyopathy, were treated with a
nonselective -receptor blocker (5 mg · kg -1 ·
day -1 propranolol) for 2 wk. Ca 2+ dynamics in isolated
cardiomyocytes of TOT mice significantly improved after treatment compared
with untreated TOT mice. Frequency-dependent diastolic and Ca 2+
transient amplitudes were returned to normal in propranolol-treated TOT mice
and but not in untreated TOT mice. Ca 2+ kinetic measurements of
time to peak and time decay of the caffeine-induced Ca 2+ transient
to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT
heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum
Ca 2+ -ATPase (SERCA), whereas Na + /Ca 2+
exchanger (NCX) concentrations were increased 2.6-fold relative to
nontransgenic samples. Propranolol treatment of TOT mice reversed the
alterations in SERCA and NCX protein levels but not potassium channels.
Although restoration of Ca 2+ dynamics occurred within 2 wk of
-blockade treatment, evidence of functional improvement in cardiac
contractility assessed by echocardiography took 10 wk to materialize. These
results demonstrate that -adrenergic blockade restores Ca 2+
dynamics and normalizes expression of Ca 2+ -handling proteins,
eventually leading to improved hemodynamic function in cardiomyopathic
hearts.
cardiomyopathy; -adrenergic receptor antagonists; dilated
Address for reprint requests and other correspondence: M. A. Sussman, Div. of
Molecular and Cardiovascular Biology, Rm. 3033, The Children's Hospital and
Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229 (E-mail:
sussman{at}heart.chmcc.org ).</description><issn>0363-6135</issn><issn>1522-1539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNqdj01OwzAUhC1URMPPCdj4AgnPdp3SbiuqHqAbVpbjvMQubhLZriBC3J0IFVixYTWL-T6NhpB7BgVjkj_ow2BRh1QALLgsOAC_INnU8JxJsZqRDEQp8pIJOSfXMR4AQC5LcUXmjJeLFSx5Rp432ht3OtJ67PTRmUhdR5NF2mjnXdfSr4k1DRhTH3RyfUerkb5XmPRHruuAHYbWmQkwOEwIrXxvXnSNt-Sy0T7i3TlvSLF92m92uXWtfXUB1WDH6Hrft6P6_qL4o1RM7QRI8Q9h_bewPXm_x7f0Y_6Kaqgb8QkONmvd</recordid><startdate>20030605</startdate><enddate>20030605</enddate><creator>Plank, David M</creator><creator>Yatani, Atsuko</creator><creator>Ritsu, Honda</creator><creator>Witt, Sandra</creator><creator>Glascock, Betty</creator><creator>Lalli, M. Jane</creator><creator>Periasamy, Muthu</creator><creator>Fiset, Celine</creator><creator>Benkusky, Nancy</creator><creator>Valdivia, Hector H</creator><creator>Sussman, Mark A</creator><scope/></search><sort><creationdate>20030605</creationdate><title>Calcium dynamics in the failing heart: restoration by {beta}-adrenergic receptor blockade</title><author>Plank, David M ; Yatani, Atsuko ; Ritsu, Honda ; Witt, Sandra ; Glascock, Betty ; Lalli, M. Jane ; Periasamy, Muthu ; Fiset, Celine ; Benkusky, Nancy ; Valdivia, Hector H ; Sussman, Mark A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-highwire_physiology_ajpheart_285_1_H3053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Plank, David M</creatorcontrib><creatorcontrib>Yatani, Atsuko</creatorcontrib><creatorcontrib>Ritsu, Honda</creatorcontrib><creatorcontrib>Witt, Sandra</creatorcontrib><creatorcontrib>Glascock, Betty</creatorcontrib><creatorcontrib>Lalli, M. Jane</creatorcontrib><creatorcontrib>Periasamy, Muthu</creatorcontrib><creatorcontrib>Fiset, Celine</creatorcontrib><creatorcontrib>Benkusky, Nancy</creatorcontrib><creatorcontrib>Valdivia, Hector H</creatorcontrib><creatorcontrib>Sussman, Mark A</creatorcontrib><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Plank, David M</au><au>Yatani, Atsuko</au><au>Ritsu, Honda</au><au>Witt, Sandra</au><au>Glascock, Betty</au><au>Lalli, M. Jane</au><au>Periasamy, Muthu</au><au>Fiset, Celine</au><au>Benkusky, Nancy</au><au>Valdivia, Hector H</au><au>Sussman, Mark A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Calcium dynamics in the failing heart: restoration by {beta}-adrenergic receptor blockade</atitle><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle><date>2003-06-05</date><risdate>2003</risdate><volume>285</volume><issue>1</issue><spage>H305</spage><pages>H305-</pages><issn>0363-6135</issn><eissn>1522-1539</eissn><abstract>Divisions of 1 Molecular Cardiovascular Biology
and 2 Cardiology, The Children's Hospital and Research
Foundation, Cincinnati 45229; 3 Department of
Physiology and Cell Biology, College of Medicine and Public Health, The Ohio
State University, Columbus, Ohio 43210;
4 Cardiovascular Research Institute and Department of
Medicine, New Jersey Medical School, University of Medicine and Dentistry of
New Jersey, Newark, New Jersey 07103; 5 Department of
Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706;
and 6 Research Center, Montreal Heart Institute,
Montreal, Quebec, Canada H1T 1C8
Submitted 20 May 2002
; accepted in final form 11 March 2003
Changes in calcium (Ca 2+ ) regulation contribute to loss of
contractile function in dilated cardiomyopathy. Clinical treatment using
-adrenergic receptor antagonists ( -blockers) slows deterioration
of cardiac function in end-stage heart failure patients; however, the effects
of -blocker treatment on Ca 2+ dynamics in the failing heart
are unknown. To address this issue, tropomodulin-overexpressing transgenic
(TOT) mice, which suffer from dilated cardiomyopathy, were treated with a
nonselective -receptor blocker (5 mg · kg -1 ·
day -1 propranolol) for 2 wk. Ca 2+ dynamics in isolated
cardiomyocytes of TOT mice significantly improved after treatment compared
with untreated TOT mice. Frequency-dependent diastolic and Ca 2+
transient amplitudes were returned to normal in propranolol-treated TOT mice
and but not in untreated TOT mice. Ca 2+ kinetic measurements of
time to peak and time decay of the caffeine-induced Ca 2+ transient
to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT
heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum
Ca 2+ -ATPase (SERCA), whereas Na + /Ca 2+
exchanger (NCX) concentrations were increased 2.6-fold relative to
nontransgenic samples. Propranolol treatment of TOT mice reversed the
alterations in SERCA and NCX protein levels but not potassium channels.
Although restoration of Ca 2+ dynamics occurred within 2 wk of
-blockade treatment, evidence of functional improvement in cardiac
contractility assessed by echocardiography took 10 wk to materialize. These
results demonstrate that -adrenergic blockade restores Ca 2+
dynamics and normalizes expression of Ca 2+ -handling proteins,
eventually leading to improved hemodynamic function in cardiomyopathic
hearts.
cardiomyopathy; -adrenergic receptor antagonists; dilated
Address for reprint requests and other correspondence: M. A. Sussman, Div. of
Molecular and Cardiovascular Biology, Rm. 3033, The Children's Hospital and
Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229 (E-mail:
sussman{at}heart.chmcc.org ).</abstract><pmid>12649072</pmid><doi>10.1152/ajpheart.00425.2002</doi></addata></record> |
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| ispartof | American journal of physiology. Heart and circulatory physiology, 2003-06, Vol.285 (1), p.H305 |
| issn | 0363-6135 1522-1539 |
| language | eng |
| recordid | cdi_highwire_physiology_ajpheart_285_1_H305 |
| source | American Physiological Society; EZB-FREE-00999 freely available EZB journals |
| title | Calcium dynamics in the failing heart: restoration by {beta}-adrenergic receptor blockade |
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