In vivo evidence against a role for adenosine in the exercise pressor reflex in humans

Departments of 1 Pharmacology-Toxicology and 2 Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Submitted 28 January 2005 ; accepted in final form 30 March 2005 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 µg·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 µmol/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 µg·min –1 ·dl –1 dipyridamole and 5 µg·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. blood pressure; microdialysis; purine nucleoside Address for reprint requests and other correspondence: N. P. Riksen, Dept. of Pharmacology-Toxicology 233, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands (E-mail: N.Riksen{at}aig.umcn.nl )