Intravascular Source of Adenosine During Forearm Ischemia in Humans

Abstract

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...

Adenosine, a Metabolic Trigger of the Exercise Pressor Reflex in Humans

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“…Adenosine samples were analyzed using a microbore HPLC system (Isco microLC system; Isco Inc) according to the method of Jackson et al 18,21 For protocol 1, MSNA was determined from the original tracings of the mean voltage neurograms using a digitizer tablet coupled to Sigma Scan software (Jandel Scientific). The amplitude of each "burst" was measured in millimeters, and total activity was defined as the sum of "burst" amplitude over 60-second periods and was expressed in arbitrary units.…”

“…[17][18][19] The probe had a dialysis tubing (10ϫ0.5 mm with a 20 000 molecular mass cutoff) and was perfused continuously with saline at a rate of 2 L/min ("perfusate") with a microinjection pump (CMA/102 Microdialysis Pump). The effluent ("dialysate") was recovered with a fraction collector.…”

Physiological Roles of Vascular Nucleoside Transporters

“…13 It is well-established that during hypoxia, extracellular adenosine levels increase and AR-dependent signaling contributes to tissue protection. 6,19,[21][22][23][24][25] However, adenosine can also be rapidly cleared from the extracellular space through passive or active uptake by NTs. 3,26 Thus, increases or decreases of NT function or expression represent an innate cellular strategy to modulate extracellular adenosine signaling.…”

Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans

“…RH has been studied most often in skeletal muscle vasculature where it is currently thought that hyperemia is due to a combination of the myogenic response (4) and local vasoactive tissue-related substances, notably prostaglandins (PGs). Other factors that appear to strongly relate to the peak flow of the hyperemic response are the local concentration of potassium (17), nitric oxide (NO) (24), adenosine (9), and endothelium-dependent hyperpolarizing factor (EDHF) (37), which have been proposed as potential mediators for the excess cumulative blood flow, i.e., the total amount of blood delivered in excess of that absent during ischemia (19). Thus RH in muscle relates to bioavailable NO, local vasodilator substances, PGs, and EDHF.…”