Document Detail


Levosimendan improves cardiac function and survival in rats with angiotensin II-induced hypertensive heart failure.
MedLine Citation:
PMID:  20811386     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Calcium-sensitizing agents improve cardiac function in acute heart failure; however, their long-term effects on cardiovascular mortality are unknown. We tested the hypothesis that levosimendan, an inodilator that acts through calcium sensitization, opening of ATP-dependent potassium channels and phosphodiesterase III inhibition, improves cardiac function and survival in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs), a model of angiotensin II (Ang II)-induced hypertensive heart failure. Levosimendan (1 mg kg(-1)) was administered orally to 4-week-old dTGRs and normotensive Sprague-Dawley rats for 4 weeks. Untreated dTGRs developed severe hypertension, cardiac hypertrophy, heart failure with impaired diastolic relaxation, and exhibited a high mortality rate at the age of 8 weeks. Levosimendan did not decrease blood pressure and did not prevent cardiac hypertrophy. However, levosimendan improved systolic function, decreased cardiac atrial natriuretic peptide mRNA expression, ameliorated Ang II-induced cardiac damage and decreased mortality. Levosimendan did not correct Ang II-induced diastolic dysfunction and did not influence heart rate. In a separate survival study, levosimendan increased dTGR survival by 58% and median survival time by 27% (P=0.004). Our findings suggest that levosimendan ameliorates Ang II-induced hypertensive heart failure and reduces mortality. The results also support the notion that the effects of levosimendan in dTGRs are mediated by blood pressure-independent mechanisms and include improved systolic function and amelioration of Ang II-induced coronary and cardiomyocyte damage.
Authors:
Agnieszka Biala; Essi Martonen; Petri Kaheinen; Jouko Levijoki; Piet Finckenberg; Saara Merasto; Marjut Louhelainen; Dominik N Muller; Friedrich C Luft; Eero Mervaala
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-02
Journal Detail:
Title:  Hypertension research : official journal of the Japanese Society of Hypertension     Volume:  33     ISSN:  1348-4214     ISO Abbreviation:  Hypertens. Res.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-05     Completed Date:  2011-02-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9307690     Medline TA:  Hypertens Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  1004-11     Citation Subset:  IM    
Affiliation:
Institute of Biomedioine, University of Helsinki, Helsinki, Finland.
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II / adverse effects*,  metabolism
Angiotensinogen / genetics,  metabolism
Animals
Blood Pressure / drug effects,  physiology
Cardiotonic Agents / pharmacology,  therapeutic use
Disease Models, Animal
Heart / drug effects,  physiology*
Heart Failure / drug therapy*,  physiopathology
Heart Rate / drug effects,  physiology
Humans
Hydrazones / pharmacology,  therapeutic use*
Hypertension / drug therapy*,  metabolism,  physiopathology
Major Histocompatibility Complex / physiology
Male
Pyridazines / pharmacology,  therapeutic use*
Rats
Rats, Sprague-Dawley
Rats, Transgenic
Renin / genetics,  metabolism
Renin-Angiotensin System / drug effects,  physiology
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
bcl-2-Associated X Protein / metabolism
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Hydrazones; 0/Pyridazines; 0/bcl-2-Associated X Protein; 11002-13-4/Angiotensinogen; 11128-99-7/Angiotensin II; 131741-08-7/simendan; EC 3.4.23.15/Renin; EC 3.6.3.8/Atp2a2 protein, rat; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases

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