Journal of Pharmacy And Bioallied Sciences
Journal of Pharmacy And Bioallied Sciences Login  | Users Online: 868  Print this pageEmail this pageSmall font sizeDefault font sizeIncrease font size 
    Home | About us | Editorial board | Search | Ahead of print | Current Issue | Past Issues | Instructions | Online submission




 
 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 13  |  Issue : 2  |  Page : 149-154  

Bidirectional relationship between covid-19 and diabetes: Role of renin–angiotensin–aldosterone system and drugs modulating it


Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman, UAE

Date of Submission12-Sep-2020
Date of Decision09-Dec-2020
Date of Acceptance22-Dec-2020
Date of Web Publication26-May-2021

Correspondence Address:
Dr. Razia Khanam
Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman
UAE
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpbs.JPBS_508_20

Rights and Permissions
   Abstract 


Numerous reports have suggested that diabetic patients are at high risk for the development of severe symptoms of coronavirus disease-2019 (COVID-19). However, a few studies have recently proposed that the relationship between diabetes and COVID-19 is bidirectional, as severe acute respiratory syndrome-coronavirus-2 also has the capability to induce diabetes. Various mechanisms have been identified and proposed to be involved in this binary association. In this review, the importance and impact of renin–angiotensin–aldosterone system (RAAS) in this two-way association of COVID-19 and diabetes has been summarized. The role and effect of drugs modulating RAAS directly or indirectly has also been discussed, as they can majorly impact the course of treatment in such patients. Further reports and data can present a clear picture of RAAS and its modulators in restoring the balance of dysregulated RAAS in COVID-19.

Keywords: Beta receptor antagonists, coronavirus, diabetes, renin–angiotensin–aldosterone system


How to cite this article:
Khanam R. Bidirectional relationship between covid-19 and diabetes: Role of renin–angiotensin–aldosterone system and drugs modulating it. J Pharm Bioall Sci 2021;13:149-54

How to cite this URL:
Khanam R. Bidirectional relationship between covid-19 and diabetes: Role of renin–angiotensin–aldosterone system and drugs modulating it. J Pharm Bioall Sci [serial online] 2021 [cited 2021 Sep 29];13:149-54. Available from: https://www.jpbsonline.org/text.asp?2021/13/2/149/316934




   Introduction Top


The emergence of severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2) in December 2019 is an extraordinary global medical challenge. Depending on the comorbidities, the symptoms and severity of previously unknown and highly contagious coronavirus disease-2019 (COVID-19) vary from patient to patient. Severity depends on multifactor including age, diabetes, cardiovascular (CV) diseases, respiratory diseases, cancer, acute kidney injury, gender, ethnicity, obesity, pro-inflammatory, and pro-coagulative state etc.[1],[2] Due to the worst prognosis of COVID-19 observed in diabetic patients, considerable attention has been directed to treatment and survival rates in both type 1 and type 2 diabetics.[3]

However, there are recent reports suggesting a two-way association between diabetes and COVID-19.[4],[5],[6] Few studies have reported that new-onset diabetes has been detected in patients of COVID-19 and also severe metabolic complications such as diabetic ketoacidosis and hyperosmolarity in patients with preexisting diabetes.[7],[8],[9] This association poses a further challenge to the medical professionals not only to understand the complex pathophysiology involved but also in the clinical management of such patients to obtain maximum therapeutic benefits.


   Why Renin–Angiotensin–Aldosterone System is Important in Bidirectional Association of Diabetes and Coronavirus Disease-2019? Top


Various researchers have already described the pathophysiological mechanisms involved in diabetes as a risk factor for severity and mortality in COVID-19.[1],[2] Enhanced secretions of glucocorticoids and catecholamines,[10] occasional hypoglycemia leading to the movement of pro-inflammatory monocytes,[11] oxidative stress involvement, and release of pro-inflammatory cytokines[12],[13] are few of them. The connotation between virus and diabetes is not at all new as hyperglycemia disrupts the control of viremia and inflammation and hence intensify mortality and morbidity.[12],[14] The risk for infections including SARS-COV2 also increases in diabetic patients, for which multiple mechanisms have been proposed.[15] A plethora of literature supports affiliation between glycemic levels and risk of being hospitalized. The previous epidemics of SARS,[16] Middle East respiratory syndrome,[17],[18],[19] and H1N1 influenza virus[20] have also confirmed the enhanced risk of viral infections in such patients. The better the glycemic control, the outcomes in infected patients are improved which highlight the need for management of optimal glycemic levels.[2]

However, only a few reports till now have speculated the possible pathophysiological mechanisms involved in the novel development of diabetes in COVID-19 patients.[6],[21] The release of cytokines and chemokines in COVID-19 triggering immune responses and damaging pancreatic beta-cells, endothelial dysfunction, glycemic fluctuations, increased intestinal permeability, increased stress and depression, etc., have been overtly mentioned in the development of new-onset diabetes mellitus (DM) in COVID-19 patients.[5],[21] Thus, in addition to the pro-inflammatory cascade induced by SARS-CoV-2, it is probable that virus may also be inducing certain pleiotropic modifications in the glycemic homeostasis, leading to the development of complications in the pathophysiology of preexisting diabetes or initiating mechanisms for the development of disease.[4],[5] What exactly can be these pleiotropic modifications, I have proposed one possible alteration in relation to renin–angiotensin–aldosterone system (RAAS) and angiotensin-converting enzyme-2 (ACE-2)/angiotensin-(1–7)/MAS axis.

SARS-CoV-2 utilizes ACE-2 as its cell receptor which is expressed in multiple organs in the body at varying levels. In addition to the other organs such as lungs, kidneys, heart, and intestines, they are also highly expressed in pancreatic β-cells and play a significant role in maintaining the balance of the body at physiological and pathophysiological level through RAAS and ACE2/angiotensin-(1–7)/MAS axis. The angiotensin-(1–7)/MAS axis upon activation by angiotensin-(1–7) produces vasodilatory, vascular protective, antifibrotic, antiproliferative, and anti-inflammatory effects. On the contrary, when angiotensin-II (Ang-II) binds to angiotensin type 1 receptor (AT1R), vasoconstriction, hypertrophy, fibrosis, proliferation, inflammation, and oxidative stress are exerted. It is interesting to know that Ang-II effects on angiotensin type 2 receptor counteract the aforesaid effects mediated by AT1R. It has been observed that SARS-COV-2 induces downregulation of ACE-2 in multiple organs, thereby producing a localized imbalance between the RAS and ACE2/angiotensin-(1–7)/MAS axis, leading to organ injuries.[21] The defensive role of ACE2/angiotensin (1–7) in diabetes was already reported by Santos et al. before the onset of COVID-19. The ACE2/angiotensin-(1–7)/MAS axis supports in improving the survival of pancreatic β-cell, stimulates insulin release, and helps in decreasing the insulin resistance.[22]

Few studies have reported elevated serum amylase and lipase levels,[23] significant changes in pancreas on computed tomography scans,[24] and the presentation of acute pancreatitis[25] in COVID-19 patient with severe symptoms. Autopsies done in 2003 have illustrated atrophy and amyloid deterioration in the majority of pancreatic islets in the SARS patients indicating the virus causes damage to the islets.[26] Needless to mention that the corticosteroids used to manage cytokine storm in such patients can induce insulin resistance and dysglycemia, interferon β-1, and other type 1 interferon can lead to autoimmune β-cell damage, and antivirals such as lopinavir/ritonavir can also produce hyperglycemia.[27] Thus, the ACE-2 dysregulation leading to the disturbance between RAAS and ACE2/angiotensin-(1–7)/MAS axis along with the disruption of protective mechanisms on pancreas and islet degeneration could be one of the primary effects that may be involved in the onset of new diabetes in COVID-19 patients.

This hypothesis is supported by the fact that Ang-II is considered a significant promoter for the development of insulin resistance and DM. The studies on diabetic animal models have shown an early enhancement in ACE2 expression as well as in its activity.[28]

[Figure 1] summarizes these observations and possible mechanisms that can lead to the onset of new diabetes mellitus in COVID-19 patients.
Figure 1: Mechanisms that can lead to the onset of new diabetes mellitus in coronavirus disease-2019 patients

Click here to view


[Figure 2] summarizes the renin–angiotensin–aldosterone system and the target of drugs acting on it.
Figure 2: The renin–angiotensin–aldosterone system and the drug targets

Click here to view



   Role and Status of Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, and Other Drugs Coronavirus Disease-2019 and Diabetes Top


Drugs acting on RAAS such as ACE inhibitors, angiotensin receptor blockers (ARBs). and aldosterone receptor blockers are the commonly prescribed drugs in CV disorders such as hypertension and congestive heart failure and in DM as well.[29] Theoretically, any drug binding/blocking ACE2 receptors will stop the entry of SARS-COV2 into the cell and henceforth the infection. Hence, clinical-grade human recombinant-soluble ACE2 have been checked endogenously and observed to block the initial stages of SARS-COV2 infection.[30] In experimental studies, the drug acting on RAAS such as ACE inhibitors, ARBs, and aldosterone receptor blockers have been shown to enhance the upregulation of ACE2 expression (which is downregulated in COVID-19). This effect leads to the strengthening of protective effects on ACE2/angiotensin-(1–7)/MAS axis.[31] Although this upregulation of ACE2 expression is till now not known in clinical studies and results are awaited, Reynolds et al. have reported the drugs acting on RAAS were not related to the significant rise in the risk for the development of severe symptoms in COVID-19 patients.[32] In an experimental study, the animal models with RAAS deactivation exhibited better symptoms in acute severe pneumonia and respiratory failure.[33]

However, few other preclinical studies have stated that usage of RAAS inhibitors might cause a compensatory induction of more ACE2, which may offer more sites of action for SARS-COV2. This effect particularly in lung infection may cause enhanced spread of COVID-19. The AT1R blockers (losartan, telmisartan, candesartan, etc.) may also can cause compensatory increase in Ang-II, leading to renoprotection.[34] The impact of RAAS inhibitors on ACE2 expression in lungs and heart is however not available.[31] Thus, both positive and negative effects can be presumed using the drugs acting/blocking RAAS.[35],[36]

Due to the nonavailability of any strong evidence of defensive or detrimental effects,[37],[38],[39] various societies such as the American Heart Association, European Society of Cardiology Council on Hypertension, and European Society of Hypertension have recommended to continue the use of ACE inhibitors or ARBs in CV disorders and DM.[15],[35] [Figure 2] summarizes the renin–angiotensin–aldosterone system and the target of drugs acting on it.


   Role of Renin–Angiotensin–Aldosterone System and Beta-Blockers Top


The sympathetic/adrenergic system works in close knit association with RAAS. Recently, it has been proposed that hyperactivity of adrenergic system-ACE2-SARS-COV2 may be involved in the primary mechanisms of COVID-19.[40] Hence, by blocking the β-receptors of adrenergic system, the activation of RAAS may also be modulated in a positive way toward reaching the therapeutic benefits in COVID-19. It is proposed that beta-receptor antagonists may reduce the ACE2 level and hence the cellular entry point for SARS-COV2 at low doses in the patients with normal blood pressure.[41] The additional effects of beta-blockers that may help further in combating COVID-19 are downregulation of CD147 cells by propranolol,[42] decrease in interleukin (IL)-6 levels, and other pro-inflammatory cytokine expression such as IL-1 β, tumor necrosis factor-alpha, interferon-γ,[40],[43] and reduction in pulmonary edema and hypercoagulation state.[40]

The role of catecholamines in aggravating the symptoms of cytokine storm has been implemented; hence, the blockade of adrenergic receptors (beta and alpha) may be helpful in counteracting the symptoms of the potentially fatal cytokine storm.[44],[45] On the other hand, the ACE2 receptor overexpression has been reported by β2-receptor agonists,[40] hence the usage of such drugs in acute respiratory distress syndrome has been recommended to be avoided.[46] By enhancing the catecholamines, the β2-receptor agonists may produce a hypercoagulable state.[47],[48],[49]

Taking all these proposed mechanisms and adrenergic receptors mediated effects into consideration, it would be interesting to know the levels of RAAS markers in COVID-19 patients to comprehend the role of sympathetic system in COVID-19 and hence its modulation. In this regard, the establishment of CoviDiab registry could be an important clinical tool to establish the degree of and illustrate new-onset, COVID-19-related diabetes, and to explore its pathogenesis, management, and outcomes.

More clinical data and retrospective studies on COVID-19 patients are required to provide clarity on issues and concerns such as:

  1. Duration of hyperglycemia/new onset diabetes after recovery: is the condition permanently established or subside with time when patient's condition improved? This is particularly more important for SARS-COV-2 as hyperglycemia has been observed to continue for up to 3 years after recovering from SARS demonstrating a transient impairment to beta cells[50]
  2. How Type 2 diabetes mellitus (T2DM) patients are managed in case when virus-induced pancreatic damage is evident: Whether T2DM patients can be still managed with antihyperglycemic/hypoglycemic agents or switched to insulin to maintain the glycemic levels?
  3. Risk of diabetic ketoacidosis or metabolic complications mainly in Type 1 diabetes mellitus patients: this is imperative to know as the patients with diabetes hospitalized for COVID-19 have been reported to be at high risk of mechanical ventilation, ICU admission, and death, due to cardiometabolic multimorbidity (CoViDiab II)[51]
  4. Role of ACE inhibitors/AT1R blockers: though the prophylactic/therapeutic benefits of these agents are not yet established, theoretically these drugs may improve the imbalance caused by the downregulation of ACE-2 receptors and disruption of ACE2/angiotensin-(1–7)/MAS axis. The effect of such drugs on glucose levels and insulin sensitivity in these patients can also provide useful information
  5. In both the conditions, i.e., diabetes (chronic uncontrolled) and COVID-19, involvement of pro-inflammatory cytokines is evident.[12],[13] In such a case, whether the use of any nonsteroidal anti-inflammatory agent could be advantageous? Nonetheless corticosteroids being hyperglycemic and insulin resistance promoters are out of the race
  6. Role of comorbidities: In a recently published case-controlled study (CoViDiab I), a high prevalence of chronic obstructive pulmonary disease and of chronic kidney disease in COVID-19 patients with Type 2 diabetes has been suggested, however cardiovascular disease frequency does not vary between people with diabetes with and without COVID-19 requiring hospitalization.[52] The comorbidities particularly CV complications such as hypertension, chronic heart failure, and metabolic disorders such as obesity, are also required to distinguish the role of RAAS in COVID-19-induced new diabetes.



   Conclusion Top


The effects and control of ACE2/angiotensin-(1–7)/MAS axis may have a crucial role in diabetes induced by SARS-COV-2. Lucidity on these issues will require careful monitoring and follow-up studies in COVID-19 patients after their recovery to fill in the gaps. As SARS-COV-2 is able to produce multiorgan damage, the recovered patients (either previously diabetic/new onset diabetic) require frequent monitoring and critical management of pulmonary, CV, neurological, and gastrointestinal systems in addition to metabolic functions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. COVID-19 in people with diabetes: Understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol 2020;8:782-92.  Back to cited text no. 1
    
2.
Zhu L, She ZG, Cheng X, Qin JJ, Zhang XJ, Cai J, et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab 2020;31:1068-77.  Back to cited text no. 2
    
3.
Tadic M, Cuspidi C, Sala C. COVID-19 and diabetes: Is there enough evidence? J Clin Hypertens (Greenwich) 2020;22:943-8.  Back to cited text no. 3
    
4.
Rubino F, Amiel SA, Zimmet P, Alberti G, Bornstein S, Eckel RH, et al. New-onset diabetes in Covid-19. N Engl J Med 2020;383:789-90.  Back to cited text no. 4
    
5.
Muthuswamy B. Does COVID 19 warn us to revisit virus induced diabetes? Explor Res Hypothesis Med 2020; 5(4):129-133 [doi: 10.14218/ERHM.2020.00046].  Back to cited text no. 5
    
6.
Mallapaty S. Mounting clues suggest the coronavirus might trigger diabetes. Nature 2020;583:16-7.  Back to cited text no. 6
    
7.
Li J, Wang X, Chen J, Zuo X, Zhang H, Deng A. COVID-19 infection may cause ketosis and ketoacidosis. Diabetes Obes Metab 2020;22:1935-41.  Back to cited text no. 7
    
8.
Chee YJ, Ng SJ, Yeoh E. Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus. Diabetes Res Clin Pract 2020;164:108166.  Back to cited text no. 8
    
9.
Heaney AI, Griffin GD, Simon EL. Newly diagnosed diabetes and diabetic ketoacidosis precipitated by COVID-19 infection. Am J Emerg Med 2020;38:2491.e3-0.  Back to cited text no. 9
    
10.
Wang A, Zhao W, Xu Z, Gu J. Timely blood glucose management for the outbreak of 2019 novel coronavirus disease (COVID-19) is urgently needed. Diabetes Res Clin Pract 2020;162:108118.  Back to cited text no. 10
    
11.
Iqbal A, Prince LR, Novodvorsky P, Bernjak A, Thomas MR, Birch L, et al. Effect of hypoglycemia on inflammatory responses and the response to low-dose endotoxemia in humans. J Clin Endocrinol Metab 2019;104:1187-99.  Back to cited text no. 11
    
12.
Knapp S. Diabetes and infection: Is there a link?--A mini-review. Gerontology 2013;59:99-104.  Back to cited text no. 12
    
13.
Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: Clinical insights and vascular mechanisms. Can J Cardiol 2018;34:575-84.  Back to cited text no. 13
    
14.
Forbes A, Murrells T, Mulnier H, Sinclair AJ. Mean HbA1c, HbA1c variability, and mortality in people with diabetes aged 70 years and older: A retrospective cohort study. Lancet Diabetes Endocrinol 2018;6:476-86.  Back to cited text no. 14
    
15.
Singh AK, Gupta R, Ghosh A, Misra A. Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations. Diabetes Metab Syndr 2020;14:303-10.  Back to cited text no. 15
    
16.
Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003;289:2801-9.  Back to cited text no. 16
    
17.
Garbati MA, Fagbo SF, Fang VJ, Skakni L, Joseph M, Wani TA, et al. A Comparative study of clinical presentation and risk factors for adverse outcome in patients hospitalised with acute respiratory disease due to MERS coronavirus or other causes. PLoS One 2016;11:e0165978.  Back to cited text no. 17
    
18.
Alqahtani FY, Aleanizy FS, Ali El Hadi Mohamed R, Alanazi MS, Mohamed N, Alrasheed MM, et al. Prevalence of comorbidities in cases of Middle East respiratory syndrome coronavirus: A retrospective study. Epidemiol Infect 2018; 147:1-5.  Back to cited text no. 18
    
19.
Banik GR, Alqahtani AS, Booy R, Rashid H. Risk factors for severity and mortality in patients with MERS-CoV: Analysis of publicly available data from Saudi Arabia. Virol Sin 2016;31:81-4.  Back to cited text no. 19
    
20.
Schoen K, Horvat N, Guerreiro NFC, de Castro I, de Giassi KS. Spectrum of clinical and radiographic findings in patients with diagnosis of H1N1 and correlation with clinical severity. BMC Infect Dis 2019;19:964.  Back to cited text no. 20
    
21.
Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care 2020;24:422.  Back to cited text no. 21
    
22.
Santos RA, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: Focus on angiotensin-(1-7). Physiol Rev 2018;98:505-53.  Back to cited text no. 22
    
23.
Pal R, Banerjee M. COVID-19 and the endocrine system: Exploring the unexplored. J Endocrinol Invest 2020;43:1027-31.  Back to cited text no. 23
    
24.
Liu F, Long X, Zhang B, Zhang W, Chen X, Zhang Z. ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection. Clin Gastroenterol Hepatol 2020;18:2128-3000.  Back to cited text no. 24
    
25.
Hadi A, Werge M, Kristiansen KT, Pedersen UG, Karstensen JG, Novovic S, et al. Coronavirus disease-19 (COVID-19) associated with severe acute pancreatitis: Case report on three family members. Pancreatology 2020;20:665-7.  Back to cited text no. 25
    
26.
Lang ZW, Zhang LJ, Zhang SJ, Meng X, Li JQ, Song CZ, et al. A clinicopathological study of three cases of severe acute respiratory syndrome (SARS). Pathology 2003;35:526-31.  Back to cited text no. 26
    
27.
Pal R, Bhadada SK. COVID-19 and diabetes mellitus: An unholy interaction of two pandemics. Diabetes Metab Syndr 2020;14:513-7.  Back to cited text no. 27
    
28.
Patel VB, Parajuli N, Oudit GY. Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications. Clin Sci (Lond) 2014;126:471-82.  Back to cited text no. 28
    
29.
Meng J, Xiao G, Zhang J, He X, Ou M, Bi J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect 2020;9:757-760.  Back to cited text no. 29
    
30.
Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020;181:905-13.  Back to cited text no. 30
    
31.
Poduri R, Joshi G, Jagadeesh G. Drugs targeting various stages of the SARS-CoV-2 life cycle: Exploring promising drugs for the treatment of Covid-19. Cell Signal 2020;74:109721.  Back to cited text no. 31
    
32.
Reynolds HR, Adhikari S, Pulgarin C, Troxel AB, Iturrate E, Johnson SB, et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19. N Engl J Med 2020;382:2441-8.  Back to cited text no. 32
    
33.
Sun ML, Yang JM, Sun YP, Su GH. Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020;43:219-22.  Back to cited text no. 33
    
34.
Gheblawi M, Wang K, Viveiros A, Gheblawi M, Wang K, Viveiros A, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2. Circ Res 2020;126:1456-74.  Back to cited text no. 34
    
35.
Rico-Mesa JS, White A, Anderson AS. Outcomes in patients with COVID-19 infection taking ACEI/ARB. Curr Cardiol Rep 2020;22:31.  Back to cited text no. 35
    
36.
Onweni CL, Zhang YS, Caulfield T, Hopkins CE, Fairweather L, Freeman WD. ACEI/ARB therapy in COVID-19: The double-edged sword of ACE2 and SARS-CoV-2 viral docking. Crit Care 2020;24:475.  Back to cited text no. 36
    
37.
Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress. Diabetes Res Clin Pract 2020;162:108142.  Back to cited text no. 37
    
38.
Bean DM, Kraljevic Z, Searle T, Bendayan R, Kevin O'G, Pickles A, et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust. Eur J Heart Fail 2020;22:967-74.  Back to cited text no. 38
    
39.
Kussmaul WG 3rd. COVID-19 and angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker therapy. Ann Intern Med 2020;173:237-8.  Back to cited text no. 39
    
40.
Vasanthakumar N. Beta-adrenergic blockers as a potential treatment for COVID-19 patients. Bioessays 2020;42:e2000094.  Back to cited text no. 40
    
41.
Vasanthakumar N. Can beta adrenergic blockers be used in the treatment of COVID 19? 2020b Sep;142:109809. doi: 10.1016/j.mehy.2020.109809.  Back to cited text no. 41
    
42.
Xie W, Xie H, Liu F, Li W, Dan J, Mei Y, et al. Propranolol induces apoptosis of human umbilical vein endothelial cells through downregulation of CD147. Br J Dermatol 2013;168:739-48.  Back to cited text no. 42
    
43.
Hajighasemi F, Mirshafiey A. In vitro effects of propranolol on T helper type 1 cytokine profile in human leukemic T cells. Int J Hematol Oncol Stem Cell Res 2016;10:99-105.  Back to cited text no. 43
    
44.
Fitzgerald PJ. Noradrenergic and serotonergic drugs may have opposing effects on COVID-19 cytokine storm and associated psychological effects. Med Hypotheses 2020;144:109985.  Back to cited text no. 44
    
45.
Konig MF, Powell MA, Staedtke V, Bai RY, Thomas DL, Fischer N, et al. Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists. J Clin Invest 2020;130:3345-7.  Back to cited text no. 45
    
46.
Sweeney RM, McAuley DF. Acute respiratory distress syndrome. Lancet 2016;388:2416-30.  Back to cited text no. 46
    
47.
Snyder EM, Wong EC, Foxx-Lupo WT, Wheatley CM, Cassuto NA, Patanwala AE. Effects of an inhaled β2-agonist on cardiovascular function and sympathetic Activity in healthy subjects. Pharmacother J Hum Pharmacol Drug Ther 2011:31:748-56.  Back to cited text no. 47
    
48.
von Känel R, Dimsdale JE. Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo. Eur J Haematol 2000;65:357-69.  Back to cited text no. 48
    
49.
Ali-Saleh M, Sarig G, Ablin JN, Brenner B, Jacob G. Inhalation of a short-acting β2-adrenoreceptor agonist induces a hypercoagulable state in healthy subjects. PLoS One 2016;11: e0158652.  Back to cited text no. 49
    
50.
Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010;47:193-9.  Back to cited text no. 50
    
51.
Maddaloni E, D'Onofrio L, Alessandri F, Mignogna C, Leto G, Pascarella G, et al. Cardiometabolic multimorbidity is associated with a worse Covid-19 prognosis than individual cardiometabolic risk factors: A multicentre retrospective study (CoViDiab II). Cardiovasc Diabetol 2020;19:164.  Back to cited text no. 51
    
52.
Maddaloni E, D'Onofrio L, Alessandri F, Mignogna C, Leto G, Coraggio L, et al. Clinical features of patients with type 2 diabetes with and without Covid 19: A case control study (CoViDiab I). Diabetes Res Clin Pract 2020;169:108454. doi: 10.1016/j.diabres.2020.108454.  Back to cited text no. 52
    


    Figures

  [Figure 1], [Figure 2]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
    Why Renin–...
    Role and Status ...
    Role of Renin...
   Conclusion
    References
    Article Figures

 Article Access Statistics
    Viewed454    
    Printed4    
    Emailed0    
    PDF Downloaded38    
    Comments [Add]    

Recommend this journal