Document Detail


Probenecid as a noninjurious positive inotrope in an ischemic heart disease murine model.
MedLine Citation:
PMID:  23241275     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The current therapeutic options for acute decompensated heart failure are limited to afterload reducers and positive inotropes. The latter increases myocardial contractility through changes in myocyte calcium (Ca²⁺) handling (mostly through stimulation of the β-adrenergic pathways [β-ADR]) and is associated with paradoxical effects of arrhythmias, cell death, and subsequently increased mortality. We have previously demonstrated that probenecid can increase cytosolic Ca²⁺ levels in the cardiomyocyte resulting in an improved inotropic response in vitro and in vivo without activating the β-ADR system. We hypothesize that, in contrast to other commonly used inotropes, probenecid functions through a system separate from that of β-ADR and hence will increase contractility and improve function without damaging the heart. Furthermore, our goal was to evaluate the effect of probenecid on cell death in vitro and its use in vivo as a positive inotrope in a mouse model of ischemic cardiomyopathy. Herein, we demonstrate that probenecid induced an influx of Ca²⁺ similar to isoproterenol, but does not induce cell death in vitro. Through a series of in vivo experiments we also demonstrate that probenecid can be used at various time points and with various methods of administration in vivo in mice with myocardial ischemia, resulting in improved contractility and no significant difference in infarct size. In conclusion, we provide novel data that probenecid, through its activity on cellular Ca²⁺ levels, induces an inotropic effect without causing or exacerbating injury. This discovery may be translatable if this mechanism is preserved in man.
Authors:
Sheryl E Koch; Michael Tranter; Nathan Robbins; Kristin Luther; Umesh Singh; Min Jiang; Xiaoping Ren; Trisha Tee; Leah Smith; Priyanka Varma; W Keith Jones; Jack Rubinstein
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-14
Journal Detail:
Title:  Journal of cardiovascular pharmacology and therapeutics     Volume:  18     ISSN:  1940-4034     ISO Abbreviation:  J. Cardiovasc. Pharmacol. Ther.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-12     Completed Date:  2013-10-29     Revised Date:  2014-05-02    
Medline Journal Info:
Nlm Unique ID:  9602617     Medline TA:  J Cardiovasc Pharmacol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  280-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Animals
Calcium Signaling / drug effects
Cardiotonic Agents / administration & dosage,  adverse effects,  pharmacology,  therapeutic use*
Cell Line
Cell Survival / drug effects
Disease Models, Animal*
Heart / drug effects*,  physiopathology
Injections, Intraperitoneal
Kinetics
Male
Membrane Transport Modulators / administration & dosage,  adverse effects,  pharmacology,  therapeutic use*
Mice
Mice, Inbred C57BL
Myocardial Contraction / drug effects
Myocardial Ischemia / drug therapy*,  prevention & control
Myocardial Reperfusion Injury / drug therapy,  pathology,  physiopathology,  prevention & control*
Myocardium / metabolism,  pathology
Probenecid / administration & dosage,  adverse effects,  pharmacology,  therapeutic use*
Random Allocation
Grant Support
ID/Acronym/Agency:
HL007382/HL/NHLBI NIH HHS; HL091478/HL/NHLBI NIH HHS; T1 UL1RR026314/RR/NCRR NIH HHS; UL1 TR000077/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Membrane Transport Modulators; PO572Z7917/Probenecid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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