MODELS OF THE DIFFUSIONAL SPREAD OF NITRIC-OXIDE - IMPLICATIONS FOR NEURAL NITRIC-OXIDE SIGNALING AND ITS PHARMACOLOGICAL PROPERTIES

Nitric oxide (NO) functions as a diffusible messenger molecule in many different tissues, including the brain. To create a conceptual framework for understanding the behaviour of NO in a biological (particularly neurobiological) scenario, we have developed theoretical,models describing the kinetic and concentration profiles for NO generated from single or multiple sources. It is predicted that the physiological sphere of influence of a single point source of NO that emits for 1-10 sec has a diameter of about 200 mu m, corresponding to a volume of brain enclosing 2 million synapses. Inactivation of NO (imposed as a half-life of 0.5-5 sec) has only relatively minor effects because diffusion is so fast. When there are multiple simultaneously-active NO sources within a tissue volume, and in the absence of decay of NO or of a time-dependent reduction in source strength, the concentration of NO simply rises linearly with time, indicating the likely importance of negative feedback by NO on NO synthesis. Distant sources (200-500 mu m away) make significant contributions to the steady-state NO concentrations in this situation even when the half-life of NO is shore (0.5-5 sec). The models predict the results of several pharmacological experiments that were interpreted to suggest that a NO-containing molecule, rather than NO itself is the endogenous messenger. Accordingly, invoking the presence of a hypothetical ''NO carrier'' on the basis of these experimental results is unnecessary.