Ongoing COVID-19 research involving endocrine targets

Role of ACE2 and inhibitors of the renin-angiotensin system

The SARS-CoV binds to the zinc peptidase ACE2, a surface molecule that is localized in the endothelial cells of arteries and veins, arterial smooth muscle, respiratory tract epithelium, epithelia of the small intestine, and immune cells, to enter the host cell. With SARS-CoV, it was shown that ACE2 overexpression facilitated viral entry and replication in cells. SARS-CoV-2 probably targets the same spectrum of cells targeted by SARS-CoV, which in the lungs are primarily localized in pneumocytes and macrophages. Acute respiratory distress syndrome (ARDS), which is the most serious complication of both SARS and COVID-19, is likely explained by this lung tropism. Moreover, extrapulmonary manifestations of COVID-19 may also be related to the systemic distribution of ACE2 in the gastrointestinal tract and the heart.

There is evidence that ACE2 expression increases on the cell membrane with the use of ACE inhibitors and angiotensin-receptor blockers. There is a theoretical concern that by increasing ACE2 expression they could facilitate the entry of virus into the host cell and increase the chances of infection or its severity. Unfortunately, data if ACE inhibitors or angiotensin-receptor blockers modify ACE2 levels or activity (or both) are lacking in experimental animal models or in humans. SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently downregulate ACE2 expression in order that the enzyme is unable to exert protective effects in organs and this may be in part responsible for organ injury in Covid-19. At present, we cannot rule out that long-term intake of ACE inhibitors and/or angiotensin-receptor blockers may facilitate SARS-CoV-2 entry and virus replication. Conversely, it is yet unknown whether intake of ACE inhibitors and/or angiotensin-receptor blockers, when infected, is beneficial with regard to pulmonary outcome. Possibly, we are dealing here with a double-edged sword, depending on the phase of the disease: increased baseline ACE2 expression could potentially rise infectivity and ACE inhibitors/ angiotensin-receptor blockers use would be an addressable risk factor. Conversely, once infected, downregulation of ACE2 may be the hallmark of COVID-19 progression. Consequently, upregulation by preferentially using renin-angiotensin system blockade and ACE2 replacement in the acute respiratory syndrome phase may turn out to be beneficial.

At present, to our knowledge, there are no peer reviewed experimental or clinical data demonstrating a specific benefit or risk of using ACE inhibitors, angiotensin-receptor blockers, or renin angiotensin aldosterone antagonists in COVID-19 patients. Moreover, abrupt withdrawal of renin angiotensin aldosterone antagonists in high-risk patients, including those who have heart failure or have had myocardial infarction, may result in clinical instability and adverse health outcomes. In this regard, the European Society of Cardiology, Council on Hypertension; American College of Cardiology, the American Heart Association and the Heart Failure Society of America and the American Society of hypertension have released policy statements strongly recommending that patients should continue treatment with their usual antihypertensive therapy because there is no clinical or empirical scientific evidence to suggest that treatment with ACE inhibitors or angiotensin receptor blockers should be discontinued because of the COVID-19 infection.

Use of oxytocin in COVID

Oxytocin exerts a dual effect by mobilizing the immune defenses, and by suppressing pathogenic responses due to overreactions of the innate immunity. In humans, in the early phases of infectious disease, oxytocin can limit the excessive proinflammatory and oxidative stress reactions, by decreasing interleukins levels. Of particular interest to Covid-19, is the nitric oxide, which is a key signaling molecule acting as a host response modulator in viral infections. In humans, activation of the oxytocin receptor, which is expressed in the pulmonary artery, can produce a vasolidatory effect. Oxytocin has been postulated as a prospective therapeutic agent for Covid-19.

Use of melatonin in COVID 19

Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin, a well-known anti-inflammatory and anti-oxidative molecule, protects against acute respiratory distress syndrome caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for COVID-19 patients. In addition, melatonin could be an adjuvant to prevent pulmonary fibrosis. Notably, melatonin has a high safety profile. There are no reports on the use of melatonin in COVID-19 to date.

Endocrinology and Metabolism: Open Access is a peer reviewed journal which focuses on the publication of current research and developments on the endocrine glands and its secretions with their coordination with metabolism and reproduction.

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Endocrinology and Metabolism: Open Access
E-Mail: endometabol@emedscholar.com