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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:109.)
© 2005 American Heart Association, Inc.

Vascular Biology

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

Niels P. Riksen; Gerard A. Rongen; Godfried H.J. Boers; Henk J. Blom; Petra H.H. van den Broek; Paul Smits

From the Departments of Pharmacology-Toxicology (N.P.R., G.A.R., P.H.H.v.d.B., P.S.), Internal Medicine (N.P.R., G.A.R., G.H.J.B., P.S.), and Pediatrics (H.J.B.), University Medical Centre Nijmegen, the Netherlands.

Correspondence to Niels P. Riksen, MD, Department of Pharmacology-Toxicology 233, University Medical Centre Nijmegen, Geert Grooteplein 21, 6525 EZ Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail N.Riksen{at}aig.umcn.nl

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<0.05). However, adenosine-induced vasodilation in the presence of dipyridamole (100 µg/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<0.0001).

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.

We postulate that a homocysteine-induced fall in extracellular adenosine contributes to the cardiovascular complications of hyperhomocysteinemia. In patients with severe hyperhomocysteinemia, we demonstrated impaired adenosine-induced vasodilation, which was restored by coinfusion of the adenosine uptake inhibitor dipyridamole. In conclusion, cellular adenosine uptake in hyperhomocysteinemia is enhanced, thereby limiting adenosine receptor stimulation.

Key Words: adenosine • hyperhomocysteinemia • dipyridamole • forearm • nucleoside transport

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