title: Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.
authors.affiliation: Mayo Clinic Cardiovascular Division, 200 First St SW, Rochester, MN 55905, USA.
authors.forename: Kalkidan
authors.initials: K
authors.lastname: Bishu
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Selma F
authors.initials: SF
authors.lastname: Mohammed
authors.forename: Martina
authors.initials: M
authors.lastname: Kruger
authors.forename: Tomohito
authors.initials: T
authors.lastname: Ohtani
authors.forename: Ozgur
authors.initials: O
authors.lastname: Ogut
authors.forename: Frank V
authors.initials: FV
authors.lastname: Brozovich
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
mesh_terms: D000367:Age Factors; D000375:Aging / Q000502:physiology; D000818:Animals; D001706:Biopsy; D003187:Compliance / Q000187:drug effects; D064211:Connectin; D006152:Cyclic GMP / Q000378:metabolism; D003971:Diastole / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D012518:Sarcomeres / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology
chemical_list: D064211:Connectin; D009124:Muscle Proteins; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D020097:Natriuretic Peptide, Brain; D000068677:Sildenafil Citrate; D011494:Protein Kinases; D006152:Cyclic GMP