Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure.

Research output: Contribution to journalArticle

  • External authors:
  • Michael Lawless
  • Jessica Caldwell
  • Emma Radcliffe
  • Charlotte Smith
  • George Madders
  • Lori Woods
  • Stephanie Church
  • Graeme Kirkwood
  • Lorenz Becker
  • Rebecca Taylor
  • Andrew Trafford

Abstract

Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment improves contractile function, reverses transverse tubule loss and restores calcium transient amplitude and the hearts response to catecholamines. Accompanying these effects tadalafil treatment normalized BNP mRNA and prevented development of subjective signs of HF. These effects are independent of changes in myocardial cGMP content and are associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterase 2 and 3. We propose that the molecular switch for the loss of transverse tubules in HF and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2A abundance following phosphodiesterase 5 inhibition.

Bibliographical metadata

Original languageEnglish
JournalScientific Reports
DOIs
Publication statusPublished - 1 May 2019

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