Understanding the therapeutic potential of phosphodiesterase 5 inhibitors for the atria
Lead Research Organisation:
University of Manchester
Department Name: School of Medical Sciences
Abstract
Similarly to the ventricle, contraction in the atria of the heart is brought about by a rise in intracellular Ca2+. The force of contraction is increased physiologically by activation of protein kinase A (PKA; via cAMP) which activates key targets including Ca2+ handling proteins and this process has been extensively studied. Protein kinase G (PKG; activated by cGMP) however also targets Ca2+ handling proteins although far less is known about its function.
Phosphodiesterases (PDEs) hydrolyze the cyclic nucleotides cGMP and cAMP and thereby modulate PKA and PKG activity in cardiac tissue. Within the working myocardium the role of PDEs modulating cAMP has been extensively studied and has been subject to clinical trials for heart failure although these were unsuccessful. The importance of PDEs targeting cGMP, specifically PDE5, has been long recognised as a treatment for erectile dysfunction and PDE5 inhibition is currently being investigated as a potential therapy for HF. Despite the emerging beneficial role of PDE5 inhibition in the ventricle in HF, the consequences of PDE5 inhibition on atrial excitation contraction coupling and ion channel function remain unknown. Interestingly a recent epidemiological study reported that patients with atrial fibrillation are less likely to die from all cause mortality when taking a PDE5 inhibitor. Our preliminary data also shows differences in the way that PDE5 inhibition affects systolic Ca2+ in the atria compared to the ventricle. This project aims to understand the functional consequences of PDE5 inhibition in atrial cells and if these could inhibit cellular correlates of arrhythmias.
Experimental questions:-
1) How does acute PDE5 inhibition modify atrial Ca homeostasis and is this pro-arrhythmic at a cellular level?
2) By what pathway are the effects of PDE5 mediated?
3) Does PDE5 treatment decrease the susceptibility of the atria to atrial fibrillation?
Phosphodiesterases (PDEs) hydrolyze the cyclic nucleotides cGMP and cAMP and thereby modulate PKA and PKG activity in cardiac tissue. Within the working myocardium the role of PDEs modulating cAMP has been extensively studied and has been subject to clinical trials for heart failure although these were unsuccessful. The importance of PDEs targeting cGMP, specifically PDE5, has been long recognised as a treatment for erectile dysfunction and PDE5 inhibition is currently being investigated as a potential therapy for HF. Despite the emerging beneficial role of PDE5 inhibition in the ventricle in HF, the consequences of PDE5 inhibition on atrial excitation contraction coupling and ion channel function remain unknown. Interestingly a recent epidemiological study reported that patients with atrial fibrillation are less likely to die from all cause mortality when taking a PDE5 inhibitor. Our preliminary data also shows differences in the way that PDE5 inhibition affects systolic Ca2+ in the atria compared to the ventricle. This project aims to understand the functional consequences of PDE5 inhibition in atrial cells and if these could inhibit cellular correlates of arrhythmias.
Experimental questions:-
1) How does acute PDE5 inhibition modify atrial Ca homeostasis and is this pro-arrhythmic at a cellular level?
2) By what pathway are the effects of PDE5 mediated?
3) Does PDE5 treatment decrease the susceptibility of the atria to atrial fibrillation?
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013751/1 | 01/10/2016 | 30/09/2025 | |||
| 1917062 | Studentship | MR/N013751/1 | 01/10/2017 | 30/04/2021 | Caitlin Waddell |