Blockade of nucleoside transport is required for delivery of intraarterial adenosine into the interstitium: relevance to therapeutic preconditioning in humans.
BACKGROUND
Adenosine, a known mediator of preconditioning, has been infused into the coronary circulation to induce therapeutic preconditioning, eg, in preparation for angioplasty. However, results have been disappointing. We tested the hypothesis that endothelial nucleoside transporter acts as a barrier impeding the delivery of intravascular adenosine into the underlying myocardium and that this can be overcome with dipyridamole, a nucleoside transporter blocker.


RESULTS
We infused saline or adenosine (0.125 and 0.5 mg/min) into the brachial artery while monitoring forearm blood flow (FBF) and interstitial adenosine levels with microdialysis probes implanted in the flexor digitorum superficialis of the forearm in 7 healthy volunteers during intravenous administration of saline or dipyridamole (loading dose, 0.142 mg/kg per min for 5 minutes followed by 0.004 mg/kg per min). Adenosine produced near maximal forearm vasodilation, increasing FBF from 4.0+/-0.7 to 10.4+/-1.9 and 13.1+/-1.6 mL/100 mL per min for the low and high doses, respectively, but did not increase muscle dialysate adenosine concentration (from 88+/-21 to 65+/-23 and 85+/-26 nmol/L). Intravenous dipyridamole enhanced resting muscle dialysate adenosine (from 77+/-25 to 147+/-50 nmol/L), adenosine-induced increase in FBF (from 4.1+/-0.8 to 12.6+/-3 and 15.1+/-3 mL/100 mL per min for the low and high dose, respectively), and the delivery of adenosine into the interstitium (to 290+/-80 and 299+/-143 nmol/L for the low and high dose, respectively, P=0.04).


CONCLUSIONS
Intravascular adenosine is likely ineffective in inducing myocardial preconditioning because of poor interstitial delivery. This can be overcome by blocking the nucleoside transporter with dipyridamole.
Gamboa
Alfredo
A
Department of Medicine, Vanderbilt University, Nashville, Tenn 37212, USA.
Ertl
Andrew C
AC
Costa
Fernando
F
Farley
Ginnie
G
Manier
M Lisa
ML
Hachey
David L
DL
Diedrich
André
A
Biaggioni
Italo
I
D000241:Adenosine / Q000008:administration & dosage* / Q000378:metabolism*; D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001916:Brachial Artery / Q000502:physiology; D004176:Dipyridamole / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism*; D005542:Forearm / Q000098:blood supply; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D007275:Injections, Intravenous; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D017551:Microdialysis; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors; D009705:Nucleosides / Q000378:metabolism*; D012016:Reference Values
D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D004176:Dipyridamole; D000241:Adenosine