Adenosine A2 receptors reverse ischemia-reperfusion lung injury independent of beta-receptors.
To evaluate the adenosine systems ability to reverse the endothelial damage produced by ischemia and reperfusion (I/R), we studied several different selective adenosine-receptor agonists and antagonists, a protein kinase A inhibitor, and a beta-adrenoreceptor antagonist in isolated buffer-perfused rat lungs. I/R (45 min/105 min) produced a sixfold increase in endothelial permeability as measured by the capillary filtration coefficient. Both a selective A2-receptor agonist (CGS-21680, 300 nM) and a beta-receptor agonist (isoproterenol, 10 microM) reversed the increased microvascular permeability. A nonselective adenosine-receptor antagonist (SPT, 20 microM) and a selective A1-receptor antagonist (DPCPX, 10 nM) had no effect on increased microvascular permeability. Also, isoproterenol and CGS-21680 reversed the damage being introduced after a selective A1-receptor agonist (CCPA, 100 nM). The nonspecific adenosine A1- and A2-receptor agonist NECA (12 nM) appeared to desensitize the A2 receptors and a protein kinase A inhibitor, adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS, 100 microM), blocked the reversal of endothelial damage by isoproterenol or A2-receptor agonist. Propranolol (100 microM) blocked the effect of isoproterenol but not the effect of CGS-21680. From this study we conclude that A2-receptor activation reverses endothelial damage associated with I/R by a mechanism independent of beta-receptors or Gi protein. However, a protein kinase A-3',5',-cyclic adenosine monophosphate pathway is activated by both the adenosine systems and beta-receptor activation.
Khimenko
P L
PL
Department of Physiology, College of Medicine, University of South Alabama, Mobile 36688, USA.
Moore
T M
TM
Hill
L W
LW
Wilson
P S
PS
Coleman
S
S
Rizzo
A
A
Taylor
A E
AE
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004727:Endothelium / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D008297:Male; D009929:Organ Size; D011652:Pulmonary Circulation; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology
D011943:Receptors, Adrenergic, beta; D018047:Receptors, Purinergic P1; D019830:Adenosine-5'-(N-ethylcarboxamide); D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine