Exploration of various administration routes for the nitric oxide donating organic nitrite, nitrosooxypropanol, in a porcine model

Organic nitrites are restricted to intravenous or inhaled administration. The aim was to explore novel administration routes for an organic nitrite, previously demonstrated to have pulmonary selectivity, in normal and elevated pulmonary vascular resistance. Hemodynamic and respiratory variables, including fraction of exhaled nitric oxide (FeNO), were measured in 13 anesthetized pigs. In naïve conditions, nitrosooxypropanol (PDNO) was given subcutaneously (100-1600 nmol/kg/min; 5 min/dose, 30 min interval), intramuscularly (50-400 nmol/kg/min; 5 min/dose, 30 min interval), intravenously (5-80 nmol/kg/min; 30 min infusion), intranasally (500-2000 nmol/kg boli), and sublingually (80-16,240 nmol/kg boli). In pulmonary hypertension (intravenous infusion of U46619), PDNO was given intravenously (5-45 nmol/kg/min; 15-20 mins infusion/dose) and subcutaneously (200-1800 nmol/kg/min; 5 min/dose at 20 min interval). Recovery was calculated using FeNO. PDNO, given by all administration routes, dose-dependently decreased systemic blood pressure and increased FeNO. Subcutaneous and intramuscular administration induced slow-onset (9 min to maximum effect) and long-lasting effects (~30 min). Intravenous administration induced rapid effects (1-2 min to steady state) and prompt decline after infusion cessation. The proportion of PDNO reaching exhaled gas (intravenous administration as reference; FeNO-based recovery) was 17% (intramuscularly) and 9% (subcutaneously). In pulmonary hypertension, intravenous and subcutaneous administration decreased the pulmonary/systemic vascular resistance-ratio. In this exploratory proof-of-concept study evaluating novel administration routes for organic nitrites, PDNO demonstrated measurable biological effects and acceptable FeNO-based recovery following intramuscular and subcutaneous administration. Furthermore, intranasal and tentatively sublingual administration showed biological effects. Future work on formulation and investigations into relevant disease models is warranted.