COVID-19: Restoring endogenous nitric oxide (NO) related homeostasis may be an effective and natural way to decrease replication of COVID-19

NO seems to inhibit the replication cycle of severe acute respiratory coronavirus. [i] It is expected that this can be exploited in some way for COVID-19 also.[ii] It is important to note that among the various biological effects of proinsulin c peptide the activation of NO production is especially well researched. C-peptide increases nitric oxide production by enhancing endothelial nitric oxide synthase (eNOS) in endothelial cells. [iii] [iv] C-peptide is capable also to increase beside eNOS the inducible nitric oxide synthase (iNOS) in smooth muscle cells. [v] Interestingly that patients with diabetes type 1, who have minimal or no pancreatic proinsulin c peptide production are among the most severely affected by the consequences of COVID-19. The mortality rate of them is increased by 350% compared to those without diabetes.[vi] The regulation and generation of NO in cardiovascular diseases (CVD) are perturbed and one of the promising ways of the treatment of CVD is to increase NO production by NO agonists. [vii] NO inhibits the recruitment of platelets to a growing thrombus. [viii] Knowing these facts it is not surprising that the risk of early mortality and of CVD in type 1 diabetes is significantly higher compared to people with type 2 diabetes.[ix]

It is an interesting possibility that centrally-intranasally administered proinsulin c-peptide may also increase NO production in various parts of the body by activating the parasympathetic nervous system.[x] [xi] [xii] [xiii] [xiv] Chronic vagus nerve stimulation can also restore decreased eNOS in an experimental animal model.[xv]

Centrally administered proinsulin c-peptide may be a promising way to decrease not only the mortality rate of patients with diabetes type 1 but also the general population with CVD.

[i] Akertström S. et al.: Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus, J Virol. 2005 Feb;79(3):1966-9.

[ii] Nampoothiri, S. et al.: The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis,

[iii] Kitamura, T., Kimura, K., Makondo, K. et al. Proinsulin C-peptide increases nitric oxide production by enhancing mitogen-activated protein-kinase-dependent transcription of endothelial nitric oxide synthase in aortic endothelial cells of Wistar rats. Diabetologia 46, 1698–1705 (2003).

[iv] Wallerath t. et al.: Stimulation of Endothelial Nitric Oxide Synthase by Proinsulin C-peptide, Nitric Oxide. 2003 Sep;9(2):95-102.

[v] Li, H. et al.: Effects of C-peptide on Expression of eNOS and iNOS in Human Cavernosal Smooth Muscle Cells, Urology. 2004 Sep;64(3):622-7.

[vi] Barron E. et al: Type 1 and Type 2 diabetes and COVID-19 related mortality in England: a whole population study,

[vii] Dobutovic B. et al.: Nitric Oxide and its Role in Cardiovascular Diseases, The Open Nitric Oxide Journal, 2011, 3, 65-71

[viii] Freedman J.E. et al.: Nitric Oxide and Its Relationship to Thrombotic Disorders,
J Thromb Haemost. 2003 Jun;1(6):1183-8.

[ix] Lee, Y., Han, K., Kim, B. et al. Risk of early mortality and cardiovascular disease in type 1 diabetes: a comparison with type 2 diabetes, a nationwide study. Cardiovasc Diabetol 18, 157 (2019).

[x] Papka, R.E., McNeill, D.L., Thompson, D. et al. Nitric oxide nerves in the uterus are parasympathetic, sensory, and contain neuropeptides. Cell Tissue Res 279, 339–349 (1995).

[xi] Nilsson S.F. et al.: Nitric Oxide as a Mediator of Parasympathetic Vasodilation in Ocular and Extraocular Tissues in the Rabbit, Invest Ophthalmol Vis Sci. 1996 Sep;37(10):2110-9.

[xii] Takahashi T. et al.: Vagal Control of Nitric Oxide and Vasoactive Intestinal Polypeptide Release in the Regulation of Gastric Relaxation in Rat, J Physiol. 1995 Apr 15;484 ( Pt 2)(Pt 2):481-92.

[xiii] Kimura K. et al.: Proinsulin C-peptide Activates Vagus Efferent Output in Rats, Peptides. 2005 Dec;26(12):2547-53.

[xiv] Johansson al.: C-peptide Improves Autonomic Nerve Function in IDDM Patients, Diabetologia. 1996 Jun;39(6):687-95.

[xv] Li, P. et al.: Chronic Vagus Nerve Stimulation Attenuates Vascular Endothelial Impairments and Reduces the Inflammatory Profile via Inhibition of the NF-κB Signaling Pathway in Ovariectomized Rats, Exp Gerontol. 2016 Feb;74:43-55.