The long-term objectives of our investigations are to gain an understanding of the regulation of retinal blood flow in the newborn, and to develop and continually expand techniques capable of measuring blood flow in this tissue. For this proposal, we will use fluorescein videoangiography, now directly validated in our laboratory, to examine our hypothesis that the purine metabolite adenosine serves as the intercellular signal between retinal neurons and their supplying microcirculation, mediating appropriate changes in retinal blood flow in response to alterations in oxygen, perfusion pressure, and glucose homeostasis. Considerable supportive evidence in favor of the involvement of adenosine in the metabolic regulation of retinal blood flow has been provided from studies in our laboratory over the last two years. Experiments proposed herein to test our hypothesis will be undertaken in a newborn pig model with endogenous intraocular pressure. The action of retinal adenosine will be modulated by selective drugs, which will be microsuffused onto the abluminal surfaces of retinal arterioles and venules. The resulting pharmacologic effect will then indicate adenosine's involvement in a particular flow response; using a similar protocol design, we also intend to identify second messengers mediating adenosine's vasodilatative effect. From the videotape record, state-of- the-art image analysis software will allow us to determine repeatedly in the same animal and velocities of selected fluorescent tracers, arteriovenous transit times, and arteriolar and venular diameters, from which we can calculate retinal blood flow. The proposed studies have considerable clinical relevance. In the newborn, disorders in the regulation of the retinal microcirculation are considered primary causative factors in the high incidence of retinopathies that continue to afflict this population. thus, it is essential to know the physiologic mechanisms controlling retinal blood flow under common, clinically-important conditions. Only then can we hope to develop therapeutic strategies for the prevention or treatment of these circulatory pathologies.
