Administration of adenosine during reperfusion reduces injury of vascular endothelium and death of myocytes

Introduction To test the hypothesis that administration of adenosine during reperfusion attenuates endothelial dysfunction and extension of infarct si ze by inhibiting polymorphonuclear neutrophil (PMN)-mediated events and apo ptosis, Methods Anesthetized dogs were subjected to 1 h coronary artery occlusion a nd 6 h of reperfusion with infusion of saline (vehicle, n=8) or 140 mu g/kg per min adenosine, n=8) continuously into the left atrium starting 5 min b efore reperfusion and continuing for 2 h, Results There was no intergroup difference in collateral myocardial blood f low measured by using colored microspheres in the area at risk during ische mia. infusion of adenosine transiently improved segmental shortening (4.1 /- 3.1% versus -2.5 +/- 2.3%, P< 0.05) and segmental work (41.4 +/- 22 vers us 15 +/- 13 mmHg/mm, P<0.05) after 4 h of reperfusion, Infusion of adenosi ne reduced size of infarct (determined by staining with triphenyltetrazoliu m chloride) from 27 +/- 2% with vehicle to 14+/-1%(P<0.05). This was confir med by measuring that it lowered activity of plasma creatine kinase (from 1 9+/-2 versus 8+/-1 IU/g protein, P<0.05). It also reduced the proportion of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-posi tive nuclei in the perinecrotic zone from 17.3 +/- 1,6 to 10.3 +/- 1.0% (P< 0.05) and reduced the appearance of DNA ladders in gel electrophoresis. In addition, it significantly decreased accumulation of PMN in the ischemic a rea (determined by immunohistochemistry with anti-CD18 antibody) and activi ty of cardiac myeloperoxidase compared with vehicle (439 +/- 52 versus 183 +/- 20 PMN/mm(2) myocardium and 1,1 +/- 0.1 versus 2.4 +/- 0.2 U/100 mg tis sue, P<0.05, respectively). Furthermore, infusion of adenosine during reper fusion preserved vascular endothelial function expressed in terms of a decr ease in adherence of PMN to postischemic coronary artery endothelium (63 +/ - 3 versus 36+/-4 PMN/mm(2) endothelium, P<0.05, basal function) and agonis t (acetylcholine)-induced endothelium-dependent relaxation (negative logari thm to base 10 of concentration (mol/l) for half-maximal effect 77 +/- 0.1 versus 7.2 +/- 0.1, P < 0.05, stimulated function). Infusion of adenosine d irectly inhibited generation of superoxide radical from canine PMN in vitro dose dependently from 27.8 +/- 6.3 to 5.8 +/- 2.1 nmol/l/5 x 10(6) PMN (P< 0.05). Conclusion Intra-atrial infusion of adenosine during reperfusion reduced ac cumulation of PMN in area at risk, preserved vascular endothelial function after ischemia reperfusion by inhibiting interaction between PMN and endoth elial cells, and decreased extension of infarct, possibly by limiting apopt osis, Coronary Artery Dis 10:617-628 (C) Lippincott Williams & Wilkins.