Membrane-Mediated Action of Phosphodiesterase 5 Inhibitors

<b>Background/Objectives</b>: Phosphodiesterase 5 (PDE5) inhibitors, sildenafil, vardenafil, and tadalafil, activate the cyclic guanosine monophosphate pathway resulting in vascular smooth muscle relaxation. They have been tested for a broad variety of conditions from cancer to Alzheimer's disease with a positive impact. The known mechanism of action of these drugs could not explain such a plethora of effects. We studied the influence of PDE5 inhibitors on lipid bilayers as a possible application point of their action. <b>Methods</b>: To monitor the membrane changes induced by PDE5 inhibitors, the differential scanning microcalorimetry and the molecular dynamics simulation were used. <b>Results</b>: We found that sildenafil, vardenafil, and tadalafil change elastic properties of model membranes: PDE5 inhibitors disorder thin membranes and order thick membranes. Moreover, PDE inhibitors were able to induce lipid interdigitation. To address the biological aspect of the findings, we performed molecular dynamics on smooth muscle cell's lipid raft treated with PDE5 inhibitors and revealed the increased density of the lipids. Furthermore, we showed that the lipid condensation in the PDE inhibitors presence increases nitric oxide permeability. <b>Conclusions</b>: The obtained results may be of biological relevance as lipid raft thickening might have an impact on membrane protein function. Moreover, improved nitric oxide flow through membrane may partially explain therapeutic action of these drugs. The presented results are useful for finding novel implications for PDE inhibitors.