Inhibition of adenosine deaminase attenuates endotoxin-induced release of cytokines in vivo in rats.
The purpose of this study was to investigate in vivo the effects of modulating the adenosine system on endotoxin-induced release of cytokines and changes in heart performance and neurohumoral status in early, profound endotoxemia in rats. Time/pressure variables of heart performance and blood pressure were recorded continuously, and plasma levels of tumor necrosis factor alpha (TNFalpha), interleukin 1-beta (IL-1beta), plasma renin activity (PRA), and catecholamines were determined before and 90 min after administration of endotoxin (30 mg/kg of lipopolysaccharide, i.v.). Erythro-9[2-hydroxyl-3-nonyl] adenine (EHNA; an adenosine deaminase inhibitor) had no effects on measured time-pressure variables of heart performance under baseline conditions and during endotoxemia, yet significantly attenuated endotoxin-induced release of cytokines and PRA. Pretreatment with the non-selective adenosine receptor antagonist DPSPX not only prevented the effects of EHNA but also increased the basal release of cytokines and augmented PRA. At baseline, caffeine (a non-selective adenosine receptor antagonist) increased HR, +dP/dtmax, heart rate x ventricular pressure product (HR x VPSP) and +dP/dtmax normalized by pressure (+dP/dtmax/VPSP), and these changes persisted during endotoxemia. Caffeine attenuated endotoxin-induced release of cytokines and augmented endotoxin-induced increases in plasma catecholamines and PRA. Pretreatment with propranolol abolished the effects of caffeine on heart performance and neurohumoral activation during the early phase of endotoxemia. 6N-cyclopentyladenosine (CPA; selective A1 adenosine receptor agonist) induced bradicardia and negative inotropic effects, reduced work load (i.e., decreased HR, VPSP, +dP/dtmax, +dP/dtmax/VPSP and HR x VPSP) and inhibited endotoxin-induced tachycardia and renin release. CGS 21680 (selective A2A adenosine receptor agonist) decreased blood pressure under basal condition but did not potentiate decreases in blood pressure during endotoxemia. CGS 21680 completely inhibited endotoxin-induced release of TNFalpha, augmented sympathetic activity and PRA, and increased +dP/dtmax and +dP/dtmax/VPSP in the absence and presence of endotoxin. The present study provides strong evidence that inhibition of adenosine deaminase reduces cytokine release in vivo without producing significant hemodynamic and cardiac effects during the early phase of profound endotoxemia in rats. The augmented neurohumoral activation induced by caffeine is associated with decreased cytokine release induced by endotoxin. Further studies are warranted to determine the impact of these effects on cardiac function and hemodynamics in the late phase of endotoxemia.
Tofovic
S P
SP
Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15213-2582, USA.
Zacharia
L
L
Carcillo
J A
JA
Jackson
E K
EK
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002395:Catecholamines / Q000097:blood; D016207:Cytokines / Q000378:metabolism*; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D004731:Endotoxins / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D011433:Propranolol / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D014970:Xanthines / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D002395:Catecholamines; D016207:Cytokines; D004731:Endotoxins; D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D002110:Caffeine; C010192:9-(2-hydroxy-3-nonyl)adenine; C053896:1,3-dipropyl-8-(4-sulfophenyl)xanthine; D011433:Propranolol; D012083:Renin; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine