| Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. | |
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MedLine Citation:
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PMID: 22144574 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-12-05 |
Journal Detail:
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Title: Circulation Volume: 124 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-20 Completed Date: 2012-02-16 Revised Date: 2013-06-12 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 2882-91 Citation Subset: AIM; IM |
Affiliation:
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Mayo Clinic Cardiovascular Division, 200 First St SW, Rochester, MN 55905, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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:
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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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