Annexin A5 scintigraphy of forearm as a novel in vivo model of skeletal muscle preconditioning in humans.
BACKGROUND
Nonlethal ischemia and reperfusion reduce ischemia-reperfusion-induced cell death, a phenomenon called ischemic preconditioning. In animal models, this potent endogenous protection is mimicked in vivo by administration of adenosine. In humans, exploitation of ischemic preconditioning is hindered by the lack of an appropriate in vivo model to study this phenomenon. To solve this problem, we aimed to set up an easy-to-use human in vivo model to study ischemic or pharmacological preconditioning.


RESULTS
Healthy male volunteers performed unilateral ischemic handgrip. At reperfusion, we intravenously injected technetium-99m-labeled Annexin A5, a presumed marker of ischemic injury, and we imaged both forearms and hands simultaneously with a gamma camera. Region of interest analysis (counts per pixel) and subsequent calculation of the percentage difference in radioactivity between experimental and control hands (thenar muscle; mean+/-SE) revealed significant uptake to the ischemically exercised tissue (26+/-3% at 4 hours after reperfusion; P<0.05). This selective localization of Annexin A5 was reduced by ischemic preconditioning (10 minutes of ischemia plus reperfusion before ischemic exercise) or by infusion of adenosine into the brachial artery to 6+/-1% and 10+/-3%, respectively (P<0.05 versus ischemic exercise alone), resembling observations in animal models with infarct size as an end point. Appropriate control experiments supported our conclusion.


CONCLUSIONS
Annexin A5 scintigraphy can be applied to test pharmacological or physiological interventions for their ability to prevent ischemia-reperfusion injury.
Rongen
Gerard A
GA
Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Center, Nijmegen, Geert Grooteplein 21, PO Box 9101, 6500 HB Nijmegen, The Netherlands. G.Rongen@pharmtox.umcn.nl
Oyen
Wim J G
WJ
Ramakers
Bart P
BP
Riksen
Niels P
NP
Boerman
Otto C
OC
Steinmetz
Neil
N
Smits
Paul
P
D000241:Adenosine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D017304:Annexin A5 / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics; D017209:Apoptosis; D004334:Drug Administration Schedule; D005080:Exercise Test; D005542:Forearm / Q000098:blood supply* / Q000000981:diagnostic imaging; D006225:Hand / Q000098:blood supply / Q000000981:diagnostic imaging; D018737:Hand Strength; D006801:Humans; D006834:Hydrazines; D006940:Hyperemia / Q000000981:diagnostic imaging; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D007511:Ischemia / Q000000981:diagnostic imaging* / Q000473:pathology; D019194:Ischemic Preconditioning; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000000981:diagnostic imaging; D009539:Nicotinic Acids; D010646:Phentolamine / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D011485:Protein Binding; D011877:Radionuclide Imaging; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics; D015427:Reperfusion Injury / Q000000981:diagnostic imaging* / Q000473:pathology / Q000517:prevention & control; D013668:Technetium Tc 99m Aggregated Albumin; D014664:Vasodilation / Q000187:drug effects
C120392:6-hydrazinopyridine-3-carboxylic acid; D017304:Annexin A5; D006834:Hydrazines; D008563:Membrane Lipids; D009539:Nicotinic Acids; D010718:Phosphatidylserines; D011994:Recombinant Proteins; D013668:Technetium Tc 99m Aggregated Albumin; D000241:Adenosine; D010646:Phentolamine