Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia

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Abstract
Objective— Endogenous adenosine has several cardioprotective effects. We postulate that in patients with hyperhomocysteinemia increased intracellular formation of S-adenosylhomocysteine decreases free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into cells through dipyridamole-sensitive transporters is enhanced, limiting adenosine receptor stimulation. We tested this hypothesis in patients with classical homocystinuria (n=9, plasma homocysteine 93.1±24.7 μmol/L) and matched controls (n=8, homocysteine 9.1±1.0). Methods and Results— Infusion of adenosine (0.5, 1.5, 5.0, and 15.0 μg/min/dL forearm) into the brachial artery increased forearm blood flow, as measured with venous occlusion plethysmography, to 2.9±0.4, 4.3±0.5, 5.6±1.1, and 9.6±2.1 in the patients and to 2.8±0.6, 4.4±1.0, 9.0±1.7, and 17.0±3.1 mL/min/dL in controls ( P P =0.9). Additionally, in isolated erythrocytes, adenosine uptake was accelerated by incubation with homocysteine (half-time 6.4±0.3 versus 8.1±0.5 minutes, P P Conclusions— In hyperhomocysteinemia, adenosine-induced vasodilation is impaired but is restored by dipyridamole. Accelerated cellular adenosine uptake probably accounts for these observations. These impaired actions of adenosine could well contribute to the cardiovascular complications of hyperhomocysteinemia.