Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection. The DEDALO project

Abstract

Background A pandemic outbreak of COVID‐19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, “cytokines storm,” that causes the systemic complications of COVID‐19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Objectives Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)‐cyclic GMP‐phosphodiesterase type 5 (PDE5) pathway in modulating low‐grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti‐inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID‐19 disease. Materials and methods We performed a systematic review of all evidence documenting any involvement of the NO‐cGMP‐PDE5 axis in the pathophysiology of COVID‐19, presenting the ongoing clinical trials aimed at modulating this axis, including our own “silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID‐19 (DEDALO trial).” Results The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID‐19 by (i) counteracting the Ang‐II‐mediated downregulation of AT‐1 receptor; (ii) acting on monocyte switching, thus reducing pro‐inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage‐necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. Discussion and Conclusion If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID‐19 in developing countries.

Addressing male sexual and reproductive health in the wake of COVID-19 outbreak

“…Additionally, by inhibiting neointimal formation and platelet aggregation, sildenafil also might prove beneficial in regard to the risk of vascular injury and thrombotic complications in COVID-19 patients [98]. Evidence from new trials will prove fundamental to assess the clinical benefits of PDE-5 inhibition on the overall burden of COVID-19 [99].…”

Hypothesis: The potential therapeutic role of nicorandil in COVID‐19

“…NO can attenuate the viral receptor (ACE2) interaction through inducing morphological changes in the viral spike (S) protein and may inhibit viral replication through diminishing viral RNA production. 43 In the absence of specific and effective therapy for COVID-19, and based on the proposed important modulatory role of NO on the interstitial lung thrombo-inflammation, NO inhalation has been suggested by some authors to be an alternative or adjuvant therapy. 44 In fact the American Food and Drug Administration (FDA) has recently granted the safety of NO-releasing drugs as a supportive therapy in COVID-19 treatment.…”

COVID-19, Type 2 Diabetes, and Hypogonadism: Lessons for Acute Management and Long-Term Prevention

“…73 These properties have been elucidated through the NO/sGC/cGMP in addition to the emerged hemeoxygenase-1 enzyme as well as hydrogen sulfide pathways. 74 PDE5 inhibitors facilitate vasoconstriction caused by AT1 receptor downregulation due to SARS-CoV-2-ACE2 binding alveolar cells, bronchial epithelium, and vascular endothelium through the NO/sGC/cGMP pathway. 74 PDE5 is expressed in high levels in the lung tissue and is highly specific for hydrolysis of cyclic guanosine monophosphate (cGMP).…”

“…74 PDE5 inhibitors facilitate vasoconstriction caused by AT1 receptor downregulation due to SARS-CoV-2-ACE2 binding alveolar cells, bronchial epithelium, and vascular endothelium through the NO/sGC/cGMP pathway. 74 PDE5 is expressed in high levels in the lung tissue and is highly specific for hydrolysis of cyclic guanosine monophosphate (cGMP). 75 Sildenafil and tadalafil are licensed as first-line treatment for pulmonary hypertension, primarily through their effect on endothelial function and prevention of impaired pulmonary artery relaxation.…”