TY  - JOUR
AU  - Riksen, N.P.
AU  - Ginneken, E.E.M. van
AU  - Broek, P.H.H. van den
AU  - Smits, P.
AU  - Rongen, G.A.P.J.M.
PY  - 2005
UR  - https://hdl.handle.net/2066/48357
AB  - The pressor response to exercise is of great importance in both physiology and pathophysiology. Whether endogenous adenosine is a trigger for this reflex remains controversial. Muscle interstitial adenosine concentration can be determined by microdialysis. However, there are indications that local muscle cell damage by the microdialysis probe confounds these measurements in exercising muscle. Therefore, we used the nucleoside uptake inhibitor dipyridamole as pharmacological tool to bypass this confounding. We used microdialysis probes to measure endogenous adenosine in forearm skeletal muscle of healthy volunteers during two cycles of 15 min of intermittent isometric handgripping. During the second contraction, dipyridamole (12 microg.min(-1).dl forearm(-1)) was administered into the brachial artery. Dipyridamole potentiated the exercise-induced increase in dialysate adenosine from 0.30 +/- 0.08 to 0.48 +/- 0.10 micromol/l (n = 9, P < 0.05), but it did not potentiate the exercise-induced increase in blood pressure. A time-control study without dipyridamole revealed no difference in exercise-induced increase in adenosine between both contractions (n = 8). To exclude the possibility that the dipyridamole-induced increase in dialysate adenosine originates from extravasation of increased circulating adenosine, we simultaneously measured adenosine with microdialysis probes in forearm muscle and antecubital vein. In a separate group of nine volunteers, simultaneous intrabrachial infusion of 100 microg.min(-1).dl(-1) dipyridamole and 5 microg.min(-1).dl(-1) adenosine increased dialysate adenosine from the intravenous but not the interstitial probe, indicating preserved endothelial barrier function for adenosine. We conclude that dipyridamole significantly inhibits uptake of interstitial adenosine without affecting the pressor response to exercise, suggesting that interstitial adenosine is not involved in the pressor response to rhythmic isometric exercise.
TI  - In vivo evidence against a role for adenosine in the exercise pressor reflex in humans.
EP  - 527
SN  - 8750-7587
IS  - iss. 2
SP  - 522
JF  - Journal of Applied Physiology
VL  - vol. 99
DO  - https://doi.org/10.1152/japplphysiol.00108.2005
ER  - 
TY  - JOUR
AU  - Riksen, N.P.
AU  - Rongen, G.A.P.J.M.
AU  - Boers, G.H.J.
AU  - Blom, H.J.
AU  - Broek, P.H.H. van den
AU  - Smits, P.
PY  - 2005
UR  - https://hdl.handle.net/2066/48279
AB  - 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<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.
TI  - Enhanced cellular adenosine uptake limits adenosine receptor stimulation in patients with hyperhomocysteinemia.
EP  - 114
SN  - 1079-5642
IS  - iss. 1
SP  - 109
JF  - Arteriosclerosis, Thrombosis, and Vascular Biology
VL  - vol. 25
DO  - https://doi.org/10.1161/01.ATV.0000150651.85907.69
L1  - https://repository.ubn.ru.nl/bitstream/handle/2066/48279/48279.pdf?sequence=1
ER  - 
TY  - JOUR
AU  - Riksen, N.P.
AU  - Oyen, W.J.G.
AU  - Ramakers, B.P.C.
AU  - Broek, P.H.H. van den
AU  - Engbersen, R.H.G.
AU  - Boerman, O.C.
AU  - Smits, P.
AU  - Rongen, G.A.P.J.M.
PY  - 2005
UR  - https://hdl.handle.net/2066/49045
AB  - BACKGROUND: Adenosine receptor stimulation induces several effects that could limit ischemia-reperfusion injury. We hypothesize that treatment with the nucleoside uptake inhibitor dipyridamole increases endogenous adenosine and limits ischemia-reperfusion injury in humans. METHODS: Ischemia-reperfusion injury was studied in forearm skeletal muscle by technetium Tc 99m-labeled annexin A5 scintigraphy. Ischemia-reperfusion injury was induced by unilateral forearm ischemic exercise. Immediately on reperfusion, annexin A5 labeled with technetium Tc 99m was administered intravenously, and ischemia-reperfusion injury was expressed as the percentage difference in radioactivity between the experimental arm and the control arm 1 and 4 hours after reperfusion. Targeting was quantified in the region of the thenar muscle and forearm flexor muscles. This approach was used in 9 healthy male volunteers after a 1-week treatment with dipyridamole (200 mg, slow release, twice daily) and in 23 control subjects. RESULTS: Dipyridamole treatment significantly reduced annexin A5 targeting in skeletal muscle compared with the control group (thenar region, 13% +/- 7% versus 22% +/- 15% at 1 hour after reperfusion and 9% +/- 6% versus 27% +/- 13% at 4 hours for dipyridamole and control groups, respectively [P = .01]; flexor region, 4% +/- 8% versus 7% +/- 6% at 1 hour after reperfusion and 1% +/- 4% versus 10% +/- 9% at 4 hours for dipyridamole and control groups, respectively [P = .01]). CONCLUSIONS: One week of oral treatment with the nucleoside uptake inhibitor dipyridamole (200 mg, slow release, twice daily) significantly limits ischemia-reperfusion injury in humans in vivo, as assessed by technetium Tc 99m-labeled annexin A5 scintigraphy of forearm skeletal muscle.
TI  - Oral therapy with dipyridamole limits ischemia-reperfusion injury in humans.
EP  - 59
SN  - 0009-9236
IS  - iss. 1
SP  - 52
JF  - Clinical Pharmacology and Therapeutics
VL  - vol. 78
DO  - https://doi.org/10.1016/j.clpt.2005.03.003
ER  -