Adenosine A1 and A2 receptor agonists reduce endotoxin-induced cellular energy depletion and oedema formation in the lung.
OBJECTIVE
Tissue depletion of adenosine during endotoxaemia has previously been described in the lung. Therapeutic approaches to prevent adenosine depletion and the role of A1 and A2 receptor agonists, however, have not been investigated until now.


METHODS
In isolated and ventilated rabbit lungs, it was tested whether pretreatment with adenosine A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 10(-7) mol, n = 6) or A2 receptor agonist 5'-(N-cyclopropyl)-carboxyamido adenosine (CPCA; 10(-7) mol, n = 6) prior to injection of lipopolysaccharide (LPS) (500 pg mL-1) influenced pulmonary artery pressure (PAP), pulmonary energy content and oedema formation as compared with controls, solely infused with LPS (n = 6). Release rates of adenosine and uric acid were determined by high-performance liquid chromatography. Pulmonary tissue concentrations of high-energy phosphates were measured and the adenine nucleotide pool, adenosine 5'-triphosphate (ATP)/adenosine 5'-diphosphate (ADP) ratio and adenylate energy charge of the pulmonary tissue were calculated.


RESULTS
Administration of LPS induced increases in PAP within 2 h up to 20.8 +/- 2.9 mmHg (P < 0.01). While pretreatment with the A1 agonist merely decelerated pressure increase (13.8 +/- 1.1 mmHg, P < 0.05), the A2 agonist completely suppressed the pulmonary pressure reaction (9.6 +/- 1.0 mmHg, P < 0.01). Emergence of lung oedema after exclusive injection of LPS up to 12.0 +/- 2.9 g was absent after A1 (0.6 +/- 0.5 g) and A2 (-0.3 +/- 0.2 g) agonists. These observations were paralleled by increased adenosine release rates compared with LPS controls (P < 0.05). Moreover, tissue concentrations of ADP, ATP, guanosine 5'-diphosphate, guanosine 5'-triphosphate, nicotinamide-adenine-dinucleotide and creatine phosphate were significantly reduced after LPS. Consequently, the calculated tissue adenine nucleotide pool and the adenylate energy charge increased after adenosine receptor stimulation (P = 0.001).


CONCLUSIONS
Adenosine A1- and A2-receptor agonists reduced LPS-induced vasoconstriction and oedema formation by maintenance of tissue energy content. Thus, adenosine receptor stimulation, in particular of the A2 receptor, might be beneficial during acute lung injury.
Heller
A R
AR
University Hospital Carl Gustav Carus, Harvard Medical International Associated Institution, Department of Anesthesiology and Intensive Care Medicine, Dresden, Germany. axel.heller@mailbox.tu-dresden.de
Rothermel
J
J
Weigand
M A
MA
Plaschke
K
K
Schmeck
J
J
Wendel
M
M
Bardenheuer
H J
HJ
Koch
T
T
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000378:metabolism / Q000517:prevention & control; D004731:Endotoxins / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects; D011654:Pulmonary Edema / Q000517:prevention & control*; D011817:Rabbits; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D012128:Respiratory Distress Syndrome / Q000378:metabolism; D013997:Time Factors; D014527:Uric Acid / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D004731:Endotoxins; D008070:Lipopolysaccharides; D018047:Receptors, Purinergic P1; D014527:Uric Acid; C058394:2-chloro-N(6)cyclopentyladenosine; C024311:N-cyclopropyl adenosine-5'-carboxamide; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000241:Adenosine