Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19.

Virus induced endothelial dysregulation is a well-recognised feature of severe Covid-19 infection. Endothelin-1 (ET-1) is the most highly expressed peptide in endothelial cells and a potent vasoconstrictor, thus representing a potential therapeutic target. ET-1 plasma levels were measured in a cohort of 194 Covid-19 patients stratified according to the clinical severity of their illness. Hospitalised patients, including those who died and those developing acute myocardial or kidney injury, had significantly elevated ET-1 plasma levels during the acute phase of infection. The results support the hypothesis that endothelin receptor antagonists may provide clinical benefit for certain Covid-19 patients.

Pulmonary artery targeted therapy in treatment of COVID-19 related ARDS. Literature review.

INTRODUCTION: The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge to improve respiratory function and help patients to survive the most challenging period. Drugs used in targeted therapy of pulmonary arterial hypertension (PAH) appears to be suitable for this task and this article describes their potential for treatment of severe cases of COVID-19. METHODS: The authors reviewed the following databases for randomized controlled trials, reviews and meta-analyses published up to July 2020: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. The authors included every study contributory to the assessment of the potential of drugs used in targeted PAH therapy in treatment of COVID-19. RESULTS: Endothelin receptor antagonists, phosphodiesterase 5 inhibitors, riociguat and prostacyclin have proven ani-inflammatory effect and reduce pulmonary artery blood pressure, lung oedema and remodelling. Bosentan shows antiviral properties and sildenafil, as well as epoprostenol, inhibits apoptosis of lung epithelial cells. Among patients with lung lesions the decrease of pulmonary blood pressure can lead to increase of ventilation/perfusion mismatch and decrease of blood oxygenation. CONCLUSIONS: Among all assessed drugs bosentan, sildenafil and epoprostenol appear to be most promising and a combination of these drugs should be considered due to synergism. The targeted PAH therapy in treatment of COVID-19 associated ARDS could be a useful tool saving lives of patients with severe SARS-CoV-2 infection, however, its introduction should be investigated and monitored very carefully as it can lead to transient deterioration of patient condition.

Endothelin antagonism and sodium glucose Co-transporter 2 inhibition. A potential combination therapeutic strategy for COVID-19.

The novel coronavirus 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic that requires a multi-faceted approach to tackle this unprecedent health crisis. Therapeutics to treat COVID-19 are an integral part of any such management strategy and there is a substantial unmet need for treatments for individuals most at risk of severe disease. This perspective review provides rationale of a combined therapeutic regimen of selective endothelin-A (ET-A) receptor antagonism and sodium glucose co-transporter-2 (SGLT-2) inhibition to treat COVID-19. Endothelin is a potent vasoconstrictor with pro-inflammatory and atherosclerotic effects. It is upregulated in a number of conditions including acute respiratory distress syndrome and cardiovascular disease. Endothelin mediates vasocontractility via endothelin (ET-A and ET-B) receptors on vascular smooth muscle cells (VSMCs). ET-B receptors regulate endothelin clearance and are present on endothelial cells, where in contrast to their role on VSMCs, mediate vasodilation. Therefore, selective endothelin-A (ET-A) receptor inhibition is likely the optimal approach to attenuate the injurious effects of endothelin and may reduce ventilation-perfusion mismatch and pulmonary inflammation, whilst improving pulmonary haemodynamics and oxygenation. SGLT-2 inhibition may dampen inflammatory cytokines, reduce hyperglycaemia if present, improve endothelial function, cardiovascular haemodynamics and cellular bioenergetics. This combination therapeutic approach may therefore have beneficial effects to mitigate both the pulmonary, metabolic and cardiorenal manifestations of COVID-19. Given these drug classes include medicines licensed to treat heart failure, diabetes and pulmonary hypertension respectively, information regarding their safety profile is established. Randomised controlled clinical trials are the best way to determine efficacy and safety of these medicines in COVID-19.

Endotheliitis, endothelin, and endothelin receptor blockers in COVID-19.

We summarize the role of endothelin as a potent vasoconstrictor, pro-inflammatory, pro-oxidative agent in the pathophysiologic effects and end-organ dysfunction of coronavirus disease 2019 (COVID-19). Endotheliitis is an under-recognized pathophysiologic process that causes various types of dysfunction in end organs, including heart, lung, kidney, and brain. Endothelin receptor blockers, such as bosentan and sitaxentan, can pave a path ahead in the realm of COVID-19 therapies. These agents have a potential role against COVID-19 and should be studied in research trials to determine their efficacy in treatment of this severe disease.

COVID-19 and Kidney Disease: Molecular Determinants and Clinical Implications in Renal Cancer.

CONTEXT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that erupted in December 2019 has affected more than a million people from over 200 countries, claiming over 70 000 lives (by April 7, 2020). As the viral infection is driven by increased angiotensin-converting enzyme-2 (ACE2) expression, with the kidney exhibiting the highest expression, it is crucial to gain insights into the mechanisms underlying renal cell carcinoma (RCC) and coronavirus disease 2019 (COVID-19). OBJECTIVE: This study considers up-to-date information on the biological determinants shared by COVID-19 and renal disease, and aims to provide evidence-based recommendations for the clinical management of RCC patients with COVID-19. EVIDENCE ACQUISITION: A literature search was performed using all sources (MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science). As of March 31, 2020, the Center for Disease Control reported that of the adults hospitalized for COVID-19 with underlying conditions in the USA, 74.8% had chronic renal disease. EVIDENCE SYNTHESIS: Evidence is discussed from epidemiological studies on SARS-CoV-2 pandemic and molecular studies on the role of kidney in facilitating routes for SARS-CoV-2 entry, leading to increased virulence of SARS-CoV-2 and clinical manifestation of symptoms in RCC. CONCLUSIONS: This analysis will advance our understanding of (1) the molecular signatures shared by RCC and COVID-19 and (2) the clinical implications of overlapping signaling pathways in the therapeutic management of RCC and COVID-19 patients. PATIENT SUMMARY: Amid the coronavirus disease 2019 (COVID-19) pandemic, patients diagnosed with renal cell carcinoma and infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may receive complimentary treatment modalities to enhance therapeutic response.