Document Detail


Direct inotropic effects of exogenous and endogenous urotensin-II: divergent actions in failing and nonfailing human myocardium.
MedLine Citation:
PMID:  19808314     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Urotensin-II (U-II) is an endogenous peptide upregulated in failing hearts. To date, insights into the myocardial actions of U-II have been obscured by its potent vasoconstrictor effects and interspecies differences in physiological responses to U-II.
METHODS AND RESULTS: We examined the direct effects of exogenous U-II on in vitro contractility in nonfailing and failing human myocardial trabeculae (n=47). Rapid cooling contractures (RCC) were used to examine sarcoplasmic reticulum Ca(2+) load. In nonfailing myocardium, exogenous U-II increased developed force (DF), rates of force generation and decline and RCC amplitude suggesting increased sarcoplasmic reticulum Ca(2+) load. In isolated myocyte suspensions from nonfailing hearts, U-II increased phospholamban phosphorylation. In failing myocardium, exogenous U-II reduced DF and rates of force generation and decline without a significant change in RCC amplitude in trabeculae or a change in phospholamban phosphorylation in myocytes. To examine the effects of endogenous U-II, we administered the peptidic U-II receptor antagonist (UT-A) GSK248451A to isolated trabeculae. UT-A induced a decrease in DF in nonfailing myocardium and an increase in DF in failing myocardium. UT-A increased RCC amplitude slightly in both nonfailing and failing myocardium. During ongoing UT-A, exogenous U-II had little effect on DF and RCC amplitude, confirming effective receptor blockade.
CONCLUSIONS: U-II modulates contractility independent of vasoconstriction with opposite effects in failing and nonfailing hearts. Positive inotropic responses to UT-A alone suggests that increased endogenous U-II constrains contractility in failing hearts via an autocrine or paracrine mechanism. These findings support a potential therapeutic role for UT-A in heart failure.
Authors:
Michael P Quaile; Hajime Kubo; Carie L Kimbrough; Stephen A Douglas; Kenneth B Margulies
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation. Heart failure     Volume:  2     ISSN:  1941-3297     ISO Abbreviation:  Circ Heart Fail     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-10-07     Completed Date:  2009-10-27     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  101479941     Medline TA:  Circ Heart Fail     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39-46     Citation Subset:  IM    
Affiliation:
Department of Physiology, Temple University School of Medicine, Philadelphia, Pa, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Blotting, Western
Enzyme Inhibitors / pharmacology
Heart Failure / metabolism*,  pathology
Humans
Middle Aged
Myocardial Contraction / drug effects*,  physiology
Myocardium / metabolism*,  pathology
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide Synthase / antagonists & inhibitors
Signal Transduction
Sodium / metabolism
Sodium-Hydrogen Antiporter / antagonists & inhibitors,  metabolism
Urotensins / metabolism*,  pharmacology*
Grant Support
ID/Acronym/Agency:
AG17022/AG/NIA NIH HHS; R01 AG017022-11/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Sodium-Hydrogen Antiporter; 0/Urotensins; 50903-99-6/NG-Nitroarginine Methyl Ester; 7440-23-5/Sodium; 9047-55-6/urotensin II; EC 1.14.13.39/Nitric Oxide Synthase
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