EFFECTIVE DIFFUSION DISTANCE OF NITRIC-OXIDE IN THE MICROCIRCULATION

Despite its well-documented importance, the mechanism for nitric oxide (NO) transport in vivo is still unclear. In particular, the effect of hemoglobin-NO interaction and the range of NO action have not been ch aracterized. in the microcirculation, where blood flow is optimally re gulated. Using a mathematical model and experimental data on NO produc tion and degradation rates, we investigated factors that determine the effective diffusion distance of NO in the microcirculation. This dist ance is defined as the distance within which NO concentration is great er than the equilibrium dissociation constant (0.25 mu M) of soluble g uanylyl cyclase, the target enzyme for NO action. We found that the si ze of the vessel is an important factor in determining the effective d iffusion distance of NO. In similar to 30- to 100-mu m-ID microvessels the luminal NO concentrations and the abluminal effective diffusion d istance are maximal. Furthermore, the model suggests that if the NO-er ythrocyte reaction rate is as fast as the rate reported for the in vit ro NO-hemoglobin reaction, the NO concentration in the vascular smooth muscle will be insufficient to stimulate smooth muscle guanylyl cycla se effectively. In addition, the existence of an erythrocyte-free laye r near the vascular wall is important in determining the effective NO diffusion distance. These results suggest that I) the range of NO acti on may exhibit significant spatial heterogeneity in vivo, depending on the size of the vessel and the local chemistry of NO degradation, 2) the NO binding/reaction constant with hemoglobin in the red blood cell may be much smaller than that with free hemoglobin, and 3) the microc irculation is the optimal site for NO to exert its regulatory function . Because NO exhibits vasodilatory function and antiatherogenic activi ty, the high NO concentration and its long effective range in the micr ocirculation may serve as intrinsic factors to prevent the development of systemic hypertension and atherosclerotic pathology in microvessel s.