Document Detail


Sildenafil prevents and reverses transverse-tubule remodeling and Ca(2+) handling dysfunction in right ventricle failure induced by pulmonary artery hypertension.
MedLine Citation:
PMID:  22203744     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Right ventricular (RV) failure (RVF) is the main cause of death in patients with pulmonary artery hypertension (PAH). Sildenafil, a phosphodiesterase type 5 inhibitor, was approved recently for treatment of PAH patients. However, the mechanisms underlying RV contractile malfunction and the benefits of sildenafil on RV function are not well understood. We aimed to investigate the following: (1) the ultrastructural and excitation-contraction coupling alterations underlying PAH-induced RVF; (2) whether the ultrastructural changes are reversible; and (3) the mechanisms underlying the therapeutic benefits of sildenafil in PAH-RVF. We used a single injection of monocrotaline in Wistar rats to induce pulmonary vascular proliferation, which led to PAH and RVF. RV myocytes displayed severe transverse (T)-tubule loss and disorganization, as well as blunted and dys-synchronous sarcoplasmic reticulum Ca(2+) release. Sildenafil prevented and reversed the monocrotaline-induced PAH and LV filling impairment. Early intervention with sildenafil prevented RV hypertrophy and the development of RVF, T-tubule remodeling, and Ca(2+) handling dysfunction. Although late treatment with sildenafil did not reverse RV hypertrophy in animals with established RVF, RV systolic function was improved. Furthermore, late intervention partially reversed both the impairment of myocyte T-tubule integrity and Ca(2+) handling protein and sarcoplasmic reticulum Ca(2+) release function in monocrotaline-treated rats. In conclusion, PAH-induced increase in RV afterload causes severe T-tubule remodeling and Ca(2+) handling dysfunction in RV myocytes, leading to RV contractile failure. Sildenafil prevents and partially reverses ultrastructural, molecular, and functional remodeling of failing RV myocytes. Reversal of pathological T-tubule remodeling, although incomplete, is achievable without the regression of RV hypertrophy.
Authors:
Yu-Ping Xie; Biyi Chen; Philip Sanders; Ang Guo; Yue Li; Kathy Zimmerman; Lie-Cheng Wang; Robert M Weiss; Isabella M Grumbach; Mark E Anderson; Long-Sheng Song
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-12-27
Journal Detail:
Title:  Hypertension     Volume:  59     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-25     Completed Date:  2012-04-20     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  355-62     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism*
Disease Models, Animal
Excitation Contraction Coupling / drug effects,  physiology
Heart Failure / etiology,  physiopathology,  prevention & control*
Hypertension, Pulmonary / chemically induced,  complications*,  physiopathology
Hypertrophy, Right Ventricular / etiology,  physiopathology,  prevention & control
Male
Microscopy, Confocal
Monocrotaline / adverse effects
Myocardial Contraction / drug effects,  physiology
Myocytes, Cardiac / drug effects,  metabolism,  pathology*
Phosphodiesterase 5 Inhibitors / pharmacology,  therapeutic use
Piperazines / pharmacology*,  therapeutic use*
Purines / pharmacology,  therapeutic use
Rats
Rats, Wistar
Sulfones / pharmacology*,  therapeutic use*
Treatment Outcome
Ventricular Dysfunction, Right / etiology,  physiopathology,  prevention & control*
Ventricular Remodeling / drug effects*,  physiology
Grant Support
ID/Acronym/Agency:
HL096652/HL/NHLBI NIH HHS; HL70250/HL/NHLBI NIH HHS; R01 HL070250/HL/NHLBI NIH HHS; R01 HL070250-10/HL/NHLBI NIH HHS; R01 HL079031/HL/NHLBI NIH HHS; R01 HL090905/HL/NHLBI NIH HHS; R01 HL090905/HL/NHLBI NIH HHS; R01 HL090905-01/HL/NHLBI NIH HHS; R01 HL090905-02/HL/NHLBI NIH HHS; R01 HL090905-02S1/HL/NHLBI NIH HHS; R01 HL090905-03/HL/NHLBI NIH HHS; R01 HL090905-04/HL/NHLBI NIH HHS; R01 HL090905-05/HL/NHLBI NIH HHS; R01 HL096652/HL/NHLBI NIH HHS; R01 HL096652-04/HL/NHLBI NIH HHS; RR026293/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Phosphodiesterase 5 Inhibitors; 0/Piperazines; 0/Purines; 0/Sulfones; 3M7OB98Y7H/sildenafil; 73077K8HYV/Monocrotaline; SY7Q814VUP/Calcium
Comments/Corrections

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