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 modulat ing the adenosine system on endotoxin-induced release of cytokines and chan ges in heart performance and neurohumoral status in early, profound endotox emia in rats. Time/pressure variables of heart performance and blood pressu re were recorded continuously, and plasma levels of tumor necrosis factor a lpha (TNF alpha), interleukin 1-beta (IL-1 beta), plasma renin activity (PR A), and catecholamines were determined before and 90 min after administrati on of endotoxin (30 mg/kg of lipopolysaccharide, Ev.). Erythro-9[2-hydroxyl -3-nonyl] adenine (EHNA; an adenosine deaminase inhibitor) had no effects o n measured time-pressure variables of heart performance under baseline cond itions and during endotoxemia, yet significantly attenuated endotoxin-induc ed release of cytokines and PRA. Pretreatment with the non-selective adenos ine receptor antagonist DPSPX not only prevented the effects of EHNA but al so increased the basal release of cytokines and augmented PRA. At baseline, caffeine (a non-selective adenosine receptor antagonist) increased HR, +dP /dt(max) heart rate x ventricular pressure product (HR x VPSP) and +dP/dt(m ax) normalized by pressure (+dP/dt(max)/VPSP), and these changes persisted during endotoxemia. Caffeine attenuated endotoxin-induced release of cytoki nes and augmented endotoxin-induced increases in plasma catecholamines and PRA. Pretreatment with propranolol abolished the effects of caffeine on hea rt performance and neurohumoral activation during the early phase of endoto xemia. 6N-cyclopentyladenosine (CPA; selective A, adenosine receptor agonis t) induced bradicardia and negative inotropic effects, reduced work load (i .e., decreased HR, VPSP, +dP/dt(max) +dP/dt(max)/VPSP and HR x VPSP) and in hibited endotoxin-induced tachycardia and renin release. CGS 21680 (selecti ve A(2A) adenosine receptor agonist) decreased blood pressure under basal c ondition but did not potentiate decreases in blood pressure during endotoxe mia. CGS 21680 completely inhibited endotoxin-induced release of TNF alpha, augmented sympathetic activity and PRA, and increased +dP/dt(max) and +dP/ dtmax/VPSP in the absence and presence of endotoxin. The present study prov ides strong evidence that inhibition of adenosine deaminase reduces cytokin e release in vivo without producing significant hemodynamic and cardiac eff ects during the early phase of profound endotoxemia in rats. The augmented neurohumoral activation induced by caffeine is associated with decreased cy tokine release induced by endotoxin. Further studies are warranted to deter mine the impact of these effects on cardiac function and hemodynamics in th e late phase of endotoxemia.