Purine nucleosides stimulate Na/K ATPase, and prolong survival in hemorrhagic shock.
BACKGROUND
Hemorrhagic shock leads to the appearance of substances in plasma that depress Na/K ATPase activity leading to a rise in plasma potassium. Recently, we reported that adenosine can stimulate Na/K ATPase activity, lower the plasma potassium back to control and prolong survival in shocked rats. However, adenosine also caused bradycardia. We therefore searched for adenosine analogs that stimulate Na/K ATPase without the side effects of bradycardia.


METHODS
Na/K ATPase activity was assessed using Rb uptake in erythrocytes. Pentobarbital anesthetized rats had their femoral artery and vein cannulated, bled to 35 mm Hg for 1 hour and resuscitated.


RESULTS
We found that the purine nucleosides, inosine, guanosine, adenosine, deoxyadenosine and deoxyguanosine, stimulated Na/K ATPase in a dose-dependent manner and overcame partial inhibition by ouabain. However, the de-ribosylated bases, the nucleotides and the pyrimidines had little or no effect on Na/K ATPase activity. Purine nucleosides did not stimulate Na/K ATPase activity through adenosine receptors, as caffeine (1 mmol/L) or aminophylline (1 mmol/L) did not block stimulation. However, stimulation was blocked by inhibitors of the equilibrative nucleoside transporter (dipyridamole, 1 mmol/L, or S-(4-nitrobenzyl)-6-thioinosine, 10 micromol/L), suggesting that the mechanism of action is intracellular. Inosine, guanosine and adenosine (2.5 mmol/L) significantly increased survival of rats in hemorrhagic shock as compared with saline and cytidine controls, and lowered the shock-elevated plasma K.


CONCLUSIONS
Purine nucleosides stimulate Na/K ATPase and prolong survival in hemorrhagic shock in rats, probably through an intracellular mechanism.
Darlington
Daniel N
DN
Department of Surgery, The Program in Trauma, University of Maryland School of Medicine, Baltimore MD 21201, USA. ddarlington@smail.umaryland.edu
Gann
Donald S
DS
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D011188:Potassium / Q000097:blood; D011684:Purine Nucleosides / Q000378:metabolism / Q000627:therapeutic use*; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D016019:Survival Analysis
D033703:Nucleoside Transport Proteins; D011684:Purine Nucleosides; D058915:Purinergic P1 Receptor Antagonists; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium