SARS-CoV-2 infects endothelial cells throughout the body with associated endothelial dysfunction, disseminated thrombosis, and endotheliitis. A hallmark of endothelial dysfunction, thrombosis, and localized inflammation is suppressed endothelial nitric oxide synthase with concomitant nitric oxide deficiency. In healthy vessels, the endothelium releases the vasodilator and antithrombotic factor, nitric oxide. Whereas in injured vessels, nitric oxide is impaired contributing to vascular collapse and thrombus formation. Jump starting endothelial nitric oxide synthase is likely time-dependent and in the case of late-stage Covid-19, endogenous nitric oxide synthase is unlikely to be up-regulated. However, providing an exogenous nitric oxide gas or stimulating the inducible nitric oxide synthase pathway early in the disease process may prove to be restorative and lifesaving. Clinicals for inhaled nitric oxide are underway and we await the outcomes.
Nitric oxide is as vital as oxygen; without it, oxygen is not delivered to our brain, muscles and organs. Nitric oxide is a pleotropic molecule: at a minimum, it lowers blood pressure and increases antimicrobial activity. As we grow older, we lose the ability to make it. And this loss of nitric oxide is further exacerbated in individuals with comorbidities, in particular, hypertension. With the onset of nitric oxide deficiencies, we see an increase in cardiometabolic problems and weakening of our innate arm of the immune system. However, biology is full of redundancies. And nitric oxide can be restored by multiple approaches: inhaled, immunostimulatory, and dietary.
Our search for a prevention and therapeutic via re-purposing current antivirals are less than impressive and a durable, scalable vaccine is a year or two away and may not play out. However, multiple strategies may be found to have merit: inhaled nitric oxide gas and BCG immunotherapy. Ironically, both are likely working through nitric oxide: nitric oxide is either pushed into our lungs via nitric oxide gas to restore pulmonary function and kill the virus directly or anti-microbial levels of nitric oxide may be triggered by the immunotherapeutic, BCG, which has been shown to be an effective immunostimulant of inducible nitric oxide synthase in preclinical models. BCG treatment of bladder cancer is speculated to be through induction of cytotoxic levels of nitric oxide.
Alternatively, several published clinicals have reported on restoring nitric oxide through diet. Hundreds of subjects have shown a reduction in blood pressure with the consumption of inorganic nitrate-rich leafy greens or beets via the dietary nitric oxide pathway, independent of nitric oxide synthase pathways. Nitric oxide can be elevated in the body with the serial reduction of inorganic nitrate from leafy green vegetables to the short-lived inorganic nitrite and S-nitrothiols which, in turn, are converted in the acidified hypoxic lungs of infected individual to nitric oxide gas, which like that of inhaled nitric oxide gas may restore pulmonary function and interferes with viral replication preventing late stage infectivity.
So, while we work on repurposing injectable antiviral drugs and strive to make durable vaccines, a dietary approach to restoring nitric oxide may have merit, especially, since it may operate at both restoring endothelial function and inhibit viral replication. The fact that coronavirus is found to be nitric oxide sensitive with identifiable nitric oxide druggable targets is worth the consideration.