Document Detail


Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo.
MedLine Citation:
PMID:  22144574     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: In vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP-activated protein kinase. Intracellular cGMP production is stimulated by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases, including phosphodiesterase-5A. We hypothesized that a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination with BNP would increase left ventricular diastolic distensibility by phosphorylating titin.
METHODS AND RESULTS: Eight elderly dogs with experimental hypertension and 4 young normal dogs underwent measurement of the end-diastolic pressure-volume relationship during caval occlusion at baseline, after sildenafil, and BNP infusion. To assess diastolic distensibility independently of load/extrinsic forces, the end-diastolic volume at a common end-diastolic pressure on the sequential end-diastolic pressure-volume relationships was measured (left ventricular capacitance). In a separate group of dogs (n=7 old hypertensive and 7 young normal), serial full-thickness left ventricular biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation. Plasma cGMP increased with sildenafil and further with BNP (7.31±2.37 to 26.9±10.3 to 70.3±8.1 pmol/mL; P<0.001). Left ventricular diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 mL; P<0.001). Changes were similar in old hypertensive and young normal dogs. There were no effects on phosphorylation of troponin I, troponin T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation increased with sildenafil and BNP, whereas titin-based cardiomyocyte stiffness decreased.
CONCLUSION: Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.
Authors:
Kalkidan Bishu; Nazha Hamdani; Selma F Mohammed; Martina Kruger; Tomohito Ohtani; Ozgur Ogut; Frank V Brozovich; John C Burnett; Wolfgang A Linke; Margaret M Redfield
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-12-05
Journal Detail:
Title:  Circulation     Volume:  124     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-20     Completed Date:  2012-02-16     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2882-91     Citation Subset:  AIM; IM    
Affiliation:
Mayo Clinic Cardiovascular Division, 200 First St SW, Rochester, MN 55905, USA.
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MeSH Terms
Descriptor/Qualifier:
Age Factors
Aging / physiology
Animals
Biopsy
Compliance / drug effects
Cyclic GMP / metabolism
Diastole / drug effects*,  physiology
Dogs
Hypertension / drug therapy*,  pathology,  physiopathology*
Muscle Proteins / metabolism*
Myocytes, Cardiac / drug effects,  pathology,  physiology
Natriuretic Peptide, Brain / pharmacology*
Phosphorylation / drug effects
Piperazines / pharmacology*
Protein Kinases / metabolism*
Purines / pharmacology
Sarcomeres / metabolism
Sulfones / pharmacology*
Vasodilator Agents / pharmacology
Ventricular Function, Left / drug effects,  physiology
Ventricular Pressure / drug effects,  physiology
Grant Support
ID/Acronym/Agency:
HL-84907/HL/NHLBI NIH HHS; HL07111-83/HL/NHLBI NIH HHS; HL63281/HL/NHLBI NIH HHS; HL76611/HL/NHLBI NIH HHS; HL78845/HL/NHLBI NIH HHS; HL78845-S1/HL/NHLBI NIH HHS; P01 HL076611/HL/NHLBI NIH HHS; R01 HL063281/HL/NHLBI NIH HHS; R01 HL078845/HL/NHLBI NIH HHS; R01 HL105418/HL/NHLBI NIH HHS; T32 HL007111/HL/NHLBI NIH HHS; U01 HL084907/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Muscle Proteins; 0/Piperazines; 0/Purines; 0/Sulfones; 0/Vasodilator Agents; 0/connectin; 114471-18-0/Natriuretic Peptide, Brain; 3M7OB98Y7H/sildenafil; 7665-99-8/Cyclic GMP; EC 2.7.-/Protein Kinases
Comments/Corrections

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