Document Detail


Heart failure switches the RV alpha1-adrenergic inotropic response from negative to positive.
MedLine Citation:
PMID:  20035030     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Right ventricular (RV) failure is a serious common clinical problem that is poorly understood. Therefore, for failing and nonfailing hearts, we examined the distinctive inotropic responses induced in the RV myocardium after the stimulation of alpha(1)-adrenergic receptors (ARs). In RV trabeculae from nonfailing mouse hearts, alpha(1)-ARs induced a negative inotropic response, consistent with our previous study. In marked contrast, in RV trabeculae from failing hearts, 12 wk after coronary artery ligation, alpha(1)-ARs induced a positive inotropic response. Mechanistically, experiments with skinned trabeculae showed that alpha(1)-ARs decreased myofilament Ca(2+) sensitivity in the nonfailing RV myocardium, whereas alpha(1)-ARs increased Ca(2+) sensitivity in heart failure. This suggests that a switch in the Ca(2+) sensitivity response to alpha(1)-AR stimulation explained the switch in the RV alpha(1)-AR inotropic response in heart failure. Myosin light chain kinase (MLCK) can increase myofilament Ca(2+) sensitivity, and the smooth muscle isoform (smMLCK), which is also present in cardiomyocytes, was more abundant in the RV myocardium from failing versus nonfailing hearts. Moreover, the MLCK inhibitor ML-9 prevented the switch of the RV myocardium to a positive alpha(1)-AR inotropic response in heart failure. In the left ventricular myocardium, in contrast, alpha(1)-AR inotropic responses were not different in failing versus nonfailing hearts, and smMLCK abundance was not increased in heart failure. In relation to human disease, we found that smMLCK mRNA and protein levels were increased in RVs from failing human hearts. We conclude that the RV inotropic response to alpha(1)-ARs is switched from negative to positive in heart failure, through a pathway involving increased myofilament Ca(2+) sensitivity. Since alpha(1)-AR agonist catecholamines are elevated in heart failure, increased alpha(1)-AR inotropic responses in the RV myocardium may be adaptive in heart failure by helping the failing RV respond to increased pulmonary pressures.
Authors:
Guan-Ying Wang; Che-Chung Yeh; Brian C Jensen; Michael J Mann; Paul C Simpson; Anthony J Baker
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-12-24
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  298     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-02-25     Completed Date:  2010-04-02     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H913-20     Citation Subset:  IM    
Affiliation:
Veterans Affairs Medical Center and Department of Medicine, University of California, San Francisco, 94121, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism
Coronary Vessels / physiopathology
Disease Models, Animal
Heart Failure / etiology,  physiopathology*
Heart Ventricles / physiopathology*
Ligation
Mice
Mice, Inbred C57BL
Myocardial Contraction / physiology*
Myocytes, Cardiac / metabolism
Myosin-Light-Chain Kinase / metabolism
Receptors, Adrenergic, alpha-1 / physiology*
Signal Transduction / physiology
Grant Support
ID/Acronym/Agency:
HL-31113/HL/NHLBI NIH HHS; HL-68738/HL/NHLBI NIH HHS; K08 HL096836-02/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Receptors, Adrenergic, alpha-1; 7440-70-2/Calcium; EC 2.7.11.18/Myosin-Light-Chain Kinase
Comments/Corrections

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