Enhanced cellular adenosine uptake limits adenosine receptor stimulation in patients with hyperhomocysteinemia.

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 micromol/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 microg/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<0.05). However, adenosine-induced vasodilation in the presence of dipyridamole (100 microg/min/dL) was similar in both groups (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<0.001) associated with increased intracellular formation of S-adenosylhomocysteine (P