4.20. Inhaled Nitric Oxide
Nitric oxide is an endogenous signaling molecule that is involved in a host of biological processes. The molecule is produced internally by the action of nitric oxide synthase enzyme that catalyzes its production from L-arginine. The antimicrobial activity of nitric oxide has been described against several protozoal and bacterial pathogens as well as against some viruses (herpes simplex virus 1, neurotropic murine coronavirus, and murine hepatitis virus strain 3) [267,268,269]. The role of nitric oxide in SARS-CoV infection was earlier investigated in Vero E6 cells by using the nitric oxide donor S-nitroso-N-acetyl-penicillamine. The study revealed that the nitric oxide donor substantially inhibited the replication of SARS-CoV in a concentration-dependent fashion (0–400 µM). Nitric oxide inhibited the viral protein and RNA synthesis. Importantly, the study demonstrated that nitric oxide produced by inducible nitric oxide synthase inhibited the replication of SARS-CoV [270]. Another study revealed that nitric oxide causes a reduction in the palmitoylation of the viral spike S protein. This subsequently impedes the fusion between the viral spike S protein and the host ACE2. Moreover, nitric oxide also leads to a substantial decrease in viral RNA production in the early steps of viral replication [271]. These outcomes were attributed to its potential effect on the cysteine proteases of SARS-CoV [272]. Given that the genome of SARS-CoV is significantly similar to SARS-CoV-2, the inhaled nitric oxide therapy in COVID-19 patients is predicted to produce the same effects [273].
Nitric oxide is also a vasodilator; thus, it has been found to promote a selective bronchodilatory effect, which may also benefit COVID-19 patients. The vasodilation is mediated by activating guanylyl cyclase. In fact, the administration of inhaled nitric oxide to critically ill patients of SARS-CoV was found to reverse pulmonary hypertension and to improve severe hypoxia. Nitric oxide administration also shortened the time needed of ventilation support [274]. Along these lines, a positive result was recently reported for inhaled nitric oxide in an outpatient with COVID-19 infection and vasoreactive idiopathic pulmonary arterial hypertension [275].
Currently, there are about 17 clinical trials being performed to evaluate the use of inhaled nitric oxide in COVID-19 patients. Other forms to indirectly deliver nitric oxide include the intravenous administration of nitrite oxide (NCT04401527; n = 200) or the nasal delivery of GLS-1200 which contains quinine diluted in saline and has been reported to stimulate nasal cells to produce nitric oxide (NCT04408183; n = 225).