Dynamic modeling and simulation of nitric oxide gas delivery to pulmonary arterioles

Nitric oxide (NO) is an effective dilator of the pulmonary arterial circulation for treatment of pulmonary hypertension. A wide range of inhalation breathing patterns and concentrations have proven effective, but the mechanisms underlying this variability are not known. We have developed a dynamic model of NO gas inhalation, which considers inhalation, diffusion, and reaction of NO in the pulmonary arteriolar region, and also considers disease progression. The response of the system (mean concentration of NO in the smooth muscle, c(sm)) is characterized using an overall transfer function. The model is used to simulate previously published experimental NO gas inhalation patterns in which a short pulse of 100 ppm of NO gas was applied at the start of inhalation. Our model predicts the clinically effective c(sm) to be 0.22-0.41 nM, which is far smaller than the equilibrium dissociation constant of soluble guanylyl cyclase previously estimated in vitro (<250 nM) and theoretically (23 nM). We conclude that the clinically effective c(sm), and the overall transfer function may be useful in the design of new NO-delivery strategies for the treatment of pulmonary hypertension.