Patient response to the Recovery trial has been remarkable: it may now have surplus statistical power for the handful of agents currently being considered. Other credible pharmaceutical agents should be introduced and patients should, as part of informed consent, be permitted open access to the reasons that the chosen agents were included or excluded from this exercise.
It is important that treatments have a credible mechanism and that they are sufficiently available for scaling beyond the trial.
Low dose PDE5 inhibitors are inexpensive, available and oral. They could be included in the trial with minimal additional work for nursing staff.
We know a little of the mode of infection of SARS-CoV2-19 and its effect on the RAAS system.
Angiotensin Converting Enzyme 1 (ACE1) cells convert Angiotensin I to its active form, Angiotensin II, which causes peripheral blood vessels to contract and helps maintain systemic (body) blood pressure. ACE inhibitors block the action of ACE1 and though their effect on ACE2 is not known, the following paradigm might explain the side effect of cough in some hypertensive patients given the drugs.
Angiotensin Converting Enzyme 2 (ACE2) cells convert active Angiotensin II to an inactive form, Angiotensin 1-7 .(1) ACE inhibitors with no known activity against ACE2 may actually lead to upregulation of ACE2. (2)
Angiotensin II causes contraction of smooth muscle via the Phosphodiesterase 5 (PDE5) pathway (3).
Thus under physiological conditions ACE2 effectively protects pulmonary smooth muscle from active Angiotensin II.
The Current Virus (SARS-COV-2) is known to target ACE2 cells in the lung (4) (5)
ACE2 is in the lower respiratory tract. At present there is no evidence that SARS-COV-2 reduces expression of ACE2 but this is an assumption that is consistent with clinical observations of the disease, COVID-19, which leads to cough and reduced oxygenation. Risk factors observed for poor outcomes in COVID-19 are associated with prior upregulation of ACE2 (2): this is consistent with the assumption that SARS-COV-2 acts by reducing expression of ACE2.
Thus SARS-COV-2 reduces ACE2 expression, thereby exposing smooth muscle in small vessels in the lung to be exposed to (vasoconstricting) Angiotensin II which acts on the vessels via PDE5, leading to some of the clinical findings in COVID-19. Vasoconstriction leads to reduce flow through the (downstream) gas exchange alveoli with the consequences of
• Reduced gas exchange and therefore reduced oxygen supply to the systemic circulation
• Reduced blood-borne immune response to the viral particles
• Increased pressure in the Pulmonary artery with shunting of deoxygenated pulmonary arterial blood to the systemic circulation.
As well as small vessel smooth muscle being exposed to the PDE5 effects of Angiotensin II, this paradigm explains the persistent dry cough of COVID19 by the same PDE5 medicated action on bronchiolar smooth muscle.
Drugs to prevent Angiotensin II having these smooth muscle effects via the PDE5 receptor are already available in the form of the PDE 5 inhibitors Sildanafil (available orally and parenterally) and Tadafil (available orally) and are considered safe enough to be sold, without prescription by pharmacies in the UK. These drugs appear to have significant promise in addressing the increased exposure of pulmonary smooth muscle to Angiotensin II in COVID-19.
1. Tikellis, C.,Thomas, M.C. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease International Journal of Peptides Volume 2012, Article ID 256294, doi:10.1155/2012/256294
2. Lei Fang, George Karakiulakis, *Michael Roth Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? www.thelancet.com/respiratory 2020 https://doi.org/10.1016/S2213-2600(20)30116-8
3. Dongsoo Kima, Toru Aizawab, Heng Weic, et al. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling J Mol Cell Cardiol. 2005 January ; 38(1): 175–184. doi:10.1016/j.yjmcc.2004.10.013
4. Hoffmann et al., 2020, Cell 181, 1–10 April 16, 2020 a 2020 Elsevier Inc. https://doi.org/10.1016/j.cell.2020.02.052,
5. Zhou, P., Yang, X., Wang, X. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). https://doi.org/10.1038/s41586-020-2012-7
Rapid Response:
It's so good it should widen it's net
Dear Editor,
Patient response to the Recovery trial has been remarkable: it may now have surplus statistical power for the handful of agents currently being considered. Other credible pharmaceutical agents should be introduced and patients should, as part of informed consent, be permitted open access to the reasons that the chosen agents were included or excluded from this exercise.
It is important that treatments have a credible mechanism and that they are sufficiently available for scaling beyond the trial.
Low dose PDE5 inhibitors are inexpensive, available and oral. They could be included in the trial with minimal additional work for nursing staff.
We know a little of the mode of infection of SARS-CoV2-19 and its effect on the RAAS system.
Angiotensin Converting Enzyme 1 (ACE1) cells convert Angiotensin I to its active form, Angiotensin II, which causes peripheral blood vessels to contract and helps maintain systemic (body) blood pressure. ACE inhibitors block the action of ACE1 and though their effect on ACE2 is not known, the following paradigm might explain the side effect of cough in some hypertensive patients given the drugs.
Angiotensin Converting Enzyme 2 (ACE2) cells convert active Angiotensin II to an inactive form, Angiotensin 1-7 .(1) ACE inhibitors with no known activity against ACE2 may actually lead to upregulation of ACE2. (2)
Angiotensin II causes contraction of smooth muscle via the Phosphodiesterase 5 (PDE5) pathway (3).
Thus under physiological conditions ACE2 effectively protects pulmonary smooth muscle from active Angiotensin II.
The Current Virus (SARS-COV-2) is known to target ACE2 cells in the lung (4) (5)
ACE2 is in the lower respiratory tract. At present there is no evidence that SARS-COV-2 reduces expression of ACE2 but this is an assumption that is consistent with clinical observations of the disease, COVID-19, which leads to cough and reduced oxygenation. Risk factors observed for poor outcomes in COVID-19 are associated with prior upregulation of ACE2 (2): this is consistent with the assumption that SARS-COV-2 acts by reducing expression of ACE2.
Thus SARS-COV-2 reduces ACE2 expression, thereby exposing smooth muscle in small vessels in the lung to be exposed to (vasoconstricting) Angiotensin II which acts on the vessels via PDE5, leading to some of the clinical findings in COVID-19. Vasoconstriction leads to reduce flow through the (downstream) gas exchange alveoli with the consequences of
• Reduced gas exchange and therefore reduced oxygen supply to the systemic circulation
• Reduced blood-borne immune response to the viral particles
• Increased pressure in the Pulmonary artery with shunting of deoxygenated pulmonary arterial blood to the systemic circulation.
As well as small vessel smooth muscle being exposed to the PDE5 effects of Angiotensin II, this paradigm explains the persistent dry cough of COVID19 by the same PDE5 medicated action on bronchiolar smooth muscle.
Drugs to prevent Angiotensin II having these smooth muscle effects via the PDE5 receptor are already available in the form of the PDE 5 inhibitors Sildanafil (available orally and parenterally) and Tadafil (available orally) and are considered safe enough to be sold, without prescription by pharmacies in the UK. These drugs appear to have significant promise in addressing the increased exposure of pulmonary smooth muscle to Angiotensin II in COVID-19.
1. Tikellis, C.,Thomas, M.C. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease International Journal of Peptides Volume 2012, Article ID 256294, doi:10.1155/2012/256294
2. Lei Fang, George Karakiulakis, *Michael Roth Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? www.thelancet.com/respiratory 2020 https://doi.org/10.1016/S2213-2600(20)30116-8
3. Dongsoo Kima, Toru Aizawab, Heng Weic, et al. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling J Mol Cell Cardiol. 2005 January ; 38(1): 175–184. doi:10.1016/j.yjmcc.2004.10.013
4. Hoffmann et al., 2020, Cell 181, 1–10 April 16, 2020 a 2020 Elsevier Inc. https://doi.org/10.1016/j.cell.2020.02.052,
5. Zhou, P., Yang, X., Wang, X. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). https://doi.org/10.1038/s41586-020-2012-7
Competing interests: No competing interests