Abstract-It is believed that adenosine is released in ischemic tissues and contributes to reactive hyperemia. We tested this hypothesis in the human forearm using microdialysis to estimate interstitial and intravascular levels of adenosine and caffeine withdrawal to potentiate endogenous adenosine and determine its effect on reactive hyperemia. Forearm blood flow response to ischemia was measured by air plethysmography before and 60 hours after the last dose of caffeine (250 mg TID for 7 days, nϭ6). Forearm blood flow increased by 274Ϯ66% and 467Ϯ97% after 3 minutes of forearm ischemia, before and during caffeine withdrawal, respectively (PϽ0.05). Thus, caffeine withdrawal enhances reactive hyperemia. To determine the source of adenosine, we measured interstitial adenosine with the use of a microdialysis probe inserted into the flexor digitorum superficialis muscle of the forearm, and we measured intravascular adenosine with the use of a microdialysis probe inserted retrogradely into the medial cubital vein. Dialysate samples were collected at 15-minute intervals during resting, forearm ischemia, and recovery periods. Forearm ischemia failed to increase muscle dialysate concentrations of adenosine but did increase intravascular dialysate adenosine 2.1-fold, from 0.61Ϯ0.12 to 1.28Ϯ0.39 mol/L (PϽ0.01, nϭ8). Intravascular dialysate concentrations of thromboxane B 2 did not increase during ischemia, ruling out platelet aggregation as a source of adenosine. These results support the hypothesis that endogenous adenosine contributes to reactive hyperemia and indicate that the major source of adenosine in the human forearm is intravascular. We speculate that endothelial cells are the source of intravascular adenosine during ischemia. (Hypertension. 1999;33:1453-1457.)Key Words: adenosine Ⅲ ischemia Ⅲ muscle Ⅲ microdialysis L ocal vasodilation is an important protective response to ischemia. This reactive hyperemia, present in all vascular beds with the exception of the kidneys, is largely due to metabolic factors produced by the mismatch between oxygen supply and metabolic demand. Adenosine has been identified as one of the metabolic products involved in this process. The contribution of adenosine to reactive hyperemia has been extensively studied in coronary circulation, 1 and adenosine has also been proposed to contribute to blood flow regulation in several other vascular beds, including skeletal muscle. [2][3][4] Because the actions of adenosine are mediated by cell membrane receptors, its importance in modulating reactive hyperemia will be proportional to the extracellular concentrations it reaches during ischemia. Adenosine is released in tissues when metabolic demands exceed oxygen supply, but extracellular concentrations are limited by efficient mechanisms of cellular uptake and metabolism. Cellular uptake is particularly potent in humans and accounts for the extremely short half-life of adenosine in blood, estimated at Ͻ1 second. 5 Previous attempts to assess how much of an increase in extracellular adenosine is...

Background: The Slitrk family of leucine-rich repeat (LRR) transmembrane proteins bears structural similarity to the Slits and the Trk receptor families, which exert well-established roles in directing nervous system development. Slitrks are less well understood, although they are highly expressed in the developing vertebrate nervous system. Moreover, slitrk variants are associated with several sensory and neuropsychiatric disorders, including myopia, deafness, obsessive-compulsive disorder (OCD), schizophrenia, and Tourette syndrome. Loss-of-function studies in mice show that Slitrks modulate neurite outgrowth and inhibitory synapse formation, although the molecular mechanisms of Slitrk function remain poorly characterized. Results: As a prelude to examining the functional roles of Slitrks, we identified eight slitrk orthologs in zebrafish and observed that seven of the eight orthologs were actively transcribed in the nervous system at embryonic, larval, and adult stages. Similar to previous findings in mice and humans, zebrafish slitrks exhibited unique but overlapping spatial and temporal expression patterns in the developing brain, retina, and spinal cord. Conclusions: Zebrafish express Slitrks in the developing central nervous system at times and locations important to neuronal morphogenesis and synaptogenesis. Future studies will use zebrafish as a convenient, cost-effective model organism to characterize the functional roles of Slitrks in nervous system development. Developmental Dynamics 243:339-349, 2014. V C 2013 Wiley Periodicals, Inc.

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