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).


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<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.
Riksen
Niels P
NP
Department of Pharmacology-Toxicology 233, University Medical Centre Nijmegen, Geert Grooteplein 21, 6525 EZ Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. N.Riksen@aig.umcn.nl
Rongen
Gerard A
GA
Boers
Godfried H J
GH
Blom
Henk J
HJ
van den Broek
Petra H H
PH
Smits
Paul
P
D000241:Adenosine / Q000378:metabolism*; D000328:Adult; D003541:Cystathionine beta-Synthase / Q000172:deficiency; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D010991:Plethysmography / Q000379:methods; D018047:Receptors, Purinergic P1 / Q000378:metabolism*
D018047:Receptors, Purinergic P1; D006710:Homocysteine; D003541:Cystathionine beta-Synthase; D000241:Adenosine